Pyrazin-2-yl-pyridin-2-yl-amine and pyrazin-2-yl-pyrimidin-4-yl-amine Compounds and Their Use

ABSTRACT

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain biarylamine compounds (referred to herein as BAA compounds), and especially certain pyrazin-2-yl-pyridin-2-yl-amine and pyrazine-2-yl-pyrimidin-4-yl-amine compounds of formula (I), which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1, that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionisiπq radiation. wherein: —X═ is independently —CR A5 ═ or —N═; and the rest of the substituents are as specified in the claims.

RELATED APPLICATIONS

This application is related to U.S. provisional patent application No.60/977,700 filed 5 Oct. 2007 and United Kingdom patent applicationnumber 0719644.7 filed 5 Oct. 2007, the contents of both of which areincorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention pertains generally to the field of therapeuticcompounds, and more specifically to certain biarylamine compounds(referred to herein as BAA compounds), and especially certainpyrazin-2-yl-pyridin-2-yl-amine and pyrazine-2-yl-pyrimidin-4-yl-aminecompounds, which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinasefunction. The present invention also pertains to pharmaceuticalcompositions comprising such compounds, and the use of such compoundsand compositions, both in vitro and in vivo, to inhibit CHK1 kinasefunction, and in the treatment of diseases and conditions that aremediated by CHK1, that are ameliorated by the inhibition of CHK1 kinasefunction, etc., including proliferative conditions such as cancer, etc.,optionally in combination with another agent, for example, (a) a DNAtopoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) anantimetabolite or TS inhibitor; (d) a microtubule targeted agent; and(e) ionising radiation.

BACKGROUND

A number of patents and publications are cited herein in order to morefully describe and disclose the invention and the state of the art towhich the invention pertains. Each of these references is incorporatedherein by reference in its entirety into the present disclosure, to thesame extent as if each individual reference was specifically andindividually indicated to be incorporated by reference.

Throughout this specification, including the claims which follow, unlessthe context requires otherwise, the word “comprise,” and variations suchas “comprises” and “comprising,” will be understood to imply theinclusion of a stated integer or step or group of integers or steps butnot the exclusion of any other integer or step or group of integers orsteps.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a pharmaceutical carrier” includes mixtures of two or moresuch carriers, and the like.

Ranges are often expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by the use of the antecedent “about,” itwill be understood that the particular value forms another embodiment.

This disclosure includes information that may be useful in understandingthe present invention. It is not an admission that any of theinformation provided herein is prior art or relevant to the presentlyclaimed invention, or that any publication specifically or implicitlyreferenced is prior art.

Checkpoint Kinase 1 (CHK1)

Progression through the cell division cycle is a tightly regulatedprocess and is monitored at several positions known as cell cyclecheckpoints (see, e.g., Weinert and Hartwell, 1989; Bartek and Lukas,2003). These checkpoints are found in all four stages of the cell cycle;G1, S (DNA replication), G2 and M (Mitosis) and they ensure that keyevents which control the fidelity of DNA replication and cell divisionare completed correctly. Cell cycle checkpoints are activated by anumber of stimuli, including DNA damage and DNA errors caused bydefective replication. When this occurs, the cell cycle will arrest,allowing time for either DNA repair to occur or, if the damage is toosevere, for activation of cellular processes leading to controlled celldeath.

All cancers, by definition, have some form of aberrant cell divisioncycle. Frequently, the cancer cells possess one or more defective cellcycle checkpoints, or harbour defects in a particular DNA repairpathway. These cells are therefore often more dependent on the remainingcell cycle checkpoints and repair pathways, compared to non-cancerouscells (where all checkpoints and DNA repair pathways are intact). Theresponse of cancer cells to DNA damage is frequently a criticaldeterminant of whether they continue to proliferate or activate celldeath processes and die. For example, tumour cells that contain a mutantform(s) of the tumour suppressor p53 are defective in the G1 DNA damagecheckpoint. Thus inhibitors of the G2 or S-phase checkpoints areexpected to further impair the ability of the tumour cell to repairdamaged DNA.

Many known cancer treatments cause DNA damage by either physicallymodifying the cell's DNA or disrupting vital cellular processes that canaffect the fidelity of DNA replication and cell division, such as DNAmetabolism, DNA synthesis, DNA transcription and microtubule spindleformation. Such treatments include for example, radiotherapy, whichcauses DNA strand breaks, and a variety of chemotherapeutic agentsincluding topoisomerase inhibitors, antimetabolites, DNA-alkylatingagents, and platinum-containing cytotoxic drugs. A significantlimitation to these genotoxic treatments is drug resistance. One of themost important mechanisms leading to this resistance is attributed toactivation of cell cycle checkpoints, giving the tumour cell time torepair damaged DNA. By abrogating a particular cell cycle checkpoint, orinhibiting a particular form of DNA repair, it may therefore be possibleto circumvent tumour cell resistance to the genotoxic agents and augmenttumour cell death induced by DNA damage, thus increasing the therapeuticindex of these cancer treatments.

CHK1 is a serine/threonine kinase involved in regulating cell cyclecheckpoint signals that are activated in response to DNA damage anderrors in DNA caused by defective replication (see, e.g., Bartek andLukas, 2003). CHK1 transduces these signals through phosphorylation ofsubstrates involved in a number of cellular activities including cellcycle arrest and DNA repair. Two key substrates of CHK1 are the Cdc25Aand Cdc25C phosphatases that dephosphorylate CDK1 leading to itsactivation, which is a requirement for exit from G2 into mitosis (Mphase) (see, e.g., Sanchez et al., 1997). Phosphorylation of Cdc25C andthe related Cdc25A by CHK1 blocks their ability to activate CDK1, thuspreventing the cell from exiting G2 into M phase. The role of CHK1 inthe DNA damage-induced G2 cell cycle checkpoint has been demonstrated ina number of studies where CHK1 function has been knocked out (see, e.g.,Liu et al., 2000; Zhao et al., 2002; Zachos et al., 2003).

The reliance of the DNA damage-induced G2 checkpoint upon CHK1 providesone example of a therapeutic strategy for cancer treatment, involvingtargeted inhibition of CHK1. Upon DNA damage, the p53 tumour suppressorprotein is stabilised and activated to give a p53-dependent G1 arrest,leading to apoptosis or DNA repair (Balaint and Vousden, 2001). Overhalf of all cancers are functionally defective for p53, which can makethem resistant to genotoxic cancer treatments such as ionising radiation(IR) and certain forms of chemotherapy (see, e.g., Greenblatt et al.,1994; Carson and Lois, 1995). These p53 deficient cells fail to arrestat the G1 checkpoint or undergo apoptosis or DNA repair, andconsequently may be more reliant on the G2 checkpoint for viability andreplication fidelity. Therefore abrogation of the G2 checkpoint throughinhibition of the CHK1 kinase function may selectively sensitise p53deficient cancer cells to genotoxic cancer therapies, and this has beendemonstrated (see, e.g., Wang et al., 1996; Dixon and Norbury, 2002).

In addition, CHK1 has also been shown to be involved in S phase cellcycle checkpoints and DNA repair by homologous recombination. Thus,inhibition of CHK1 kinase in those cancers that are reliant on theseprocesses after DNA damage, may provide additional therapeuticstrategies for the treatment of cancers using CHK1 inhibitors (see,e.g., Sorensen et al., 2005). Recent data using CHK1 selective siRNAsupports the selective inhibition of CHK1 as a relevant therapeuticapproach, and suggests that combined inhibition with certain othercheckpoint kinases provides no additional benefit and may benon-productive (see, e.g., Xiao et al., 2006). Small-molecule selectiveinhibitors of CHK1 kinase function from various chemical classes havebeen described (see, e.g., Tao and Lin, 2006).

Wang et al., 2005, describe certain pyrazine compounds of the followingformula which allegedly are useful as potassium ion channel modulators.

SUMMARY OF THE INVENTION

One aspect of the invention pertains to certain biarylamine compounds(referred to herein as BAA compounds), as described herein.

Another aspect of the invention pertains to a composition (e.g., apharmaceutical composition) comprising a BAA compound, as describedherein, and a pharmaceutically acceptable carrier or diluent.

Another aspect of the invention pertains to method of preparing acomposition (e.g., a pharmaceutical composition) comprising the step ofadmixing a BAA compound, as described herein, and a pharmaceuticallyacceptable carrier or diluent.

Another aspect of the present invention pertains to a method ofinhibiting CHK1 kinase function in a cell, in vitro or in vivo,comprising contacting the cell with an effective amount of a BAAcompound, as described herein.

In one embodiment, the method further comprises contacting the cell withone or more other agents selected from: (a) a DNA topoisomerase I or IIinhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TSinhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Another aspect of the present invention pertains to a method ofregulating (e.g., inhibiting) cell proliferation (e.g., proliferation ofa cell), inhibiting cell cycle progression, promoting apoptosis, or acombination of one or more these, in vitro or in vivo, comprisingcontacting a cell with an effective amount of a BAA compound, asdescribed herein.

In one embodiment, the method further comprises contacting the cell withone or more other agents selected from: (a) a DNA topoisomerase I or IIinhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TSinhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Another aspect of the present invention pertains to a method oftreatment comprising administering to a subject in need of treatment atherapeutically-effective amount of a BAA compound, as described herein,preferably in the form of a pharmaceutical composition.

In one embodiment, the method further comprises administering to thesubject one or more other agents selected from: (a) a DNA topoisomeraseI or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TSinhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Another aspect of the present invention pertains to a BAA compound asdescribed herein for use in a method of treatment of the human or animalbody by therapy.

In one embodiment, the method of treatment comprises treatment with both(i) a BAA compound and (ii) one or more other agents selected from: (a)a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) anantimetabolite or TS inhibitor; (d) a microtubule targeted agent; and(e) ionising radiation.

Another aspect of the present invention pertains to use of a BAAcompound, as described herein, in the manufacture of a medicament foruse in treatment.

In one embodiment, the treatment comprises treatment with both (i) amedicament comprising a BAA compound and (ii) one or more other agentsselected from: (a) a DNA topoisomerase I or II inhibitor; (b) a DNAdamaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubuletargeted agent; and (e) ionising radiation.

In one embodiment, the treatment is treatment of a disease or conditionthat is mediated by CHK1.

In one embodiment, the treatment is treatment of a disease or conditionthat is ameliorated by the inhibition of CHK1 kinase function.

In one embodiment, the treatment is treatment of a proliferativecondition.

In one embodiment, the treatment is treatment of cancer.

In one embodiment, the treatment is treatment of: p53 negative cancer.

In one embodiment, the treatment is treatment of: lung cancer, breastcancer, ovarian cancer, colorectal cancer, melanoma, or glioma.

Another aspect of the present invention pertains to a kit comprising (a)a BAA compound, as described herein, preferably provided as apharmaceutical composition and in a suitable container and/or withsuitable packaging; and (b) instructions for use, for example, writteninstructions on how to administer the compound.

In one embodiment, the kit further comprises one or more other agentsselected from: (a) a DNA topoisomerase I or II inhibitor; (b) a DNAdamaging agent; (c) an antimetabolite or TS inhibitor; and (d) amicrotubule targeted agent.

Another aspect of the present invention pertains to a BAA compoundobtainable by a method of synthesis as described herein, or a methodcomprising a method of synthesis as described herein.

Another aspect of the present invention pertains to a BAA compoundobtained by a method of synthesis as described herein, or a methodcomprising a method of synthesis as described herein.

Another aspect of the present invention pertains to novel intermediates,as described herein, which are suitable for use in the methods ofsynthesis described herein.

Another aspect of the present invention pertains to the use of suchnovel intermediates, as described herein, in the methods of synthesisdescribed herein.

As will be appreciated by one of skill in the art, features andpreferred embodiments of one aspect of the invention will also pertainto other aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

One aspect of the present invention relates to certain biarylamines (forconvenience, collectively referred to herein as “biarylamine compounds”or “BAA compounds”) which are pyrazin-2-yl-pyridin-2-yl-amines orpyrazine-2-yl-pyrimidin-4-yl-amines.

In one embodiment, the compounds are selected from compounds of thefollowing formula, and pharmaceutically acceptable salts, solvates,chemically protected forms, and prodrugs thereof:

wherein:

-   -   —X═ is independently —CR^(A5)═ or —N═;    -   —R^(A5) is independently —H or -Q^(A5);    -   —R^(A3) is independently —H or -Q^(A3);    -   —R^(A4) is independently —NH₂, -Q^(A4N), —OH, —O-Q^(A4O), —SH,        or —S-Q^(A4S);    -   —R^(B3) is independently —H or -Q^(B3);    -   —R^(B5) is independently —H or -Q^(B5); and    -   —R^(B6) is independently —H or -Q^(B6).

The Group —X═

In one embodiment, —X═ is independently —CR^(A5)═ or —N═.

In one embodiment, —X═ is independently —CR^(A5)═.

In one embodiment, —X═ is independently —N═.

The Group —R^(A5)

In one embodiment, —R^(A5), if present, is independently —H or -Q^(A5).

In one embodiment, —R^(A5), if present, is independently —H.

In one embodiment, —R^(A5), if present, is independently -Q^(A5).

The Group —R^(A3)

In one embodiment, —R^(A3) is independently —H or -Q^(A3).

In one embodiment, —R^(A3) is independently —H.

In one embodiment, —R^(A3) is independently -Q^(A3).

The Group —R^(A4)

In one embodiment, —R^(A4) is independently —NH₂, -Q^(A4N), —OH,—O-Q^(A4O), —SH, or —S-Q^(A4S).

In one embodiment, —R^(A4) is independently —NH₂ or -Q^(A4N).

In one embodiment, —R^(A4) is independently -Q^(A4N).

In one embodiment, —R^(A4) is independently —NH₂.

In one embodiment, —R^(A4) is independently —OH or —O-Q^(A4O).

In one embodiment, —R^(A4) is independently —OH.

In one embodiment, —R^(A4) is independently —O-Q^(A4O).

In one embodiment, —R^(A4) is independently —SH or —S-Q^(A4S).

In one embodiment, —R^(A4) is independently —SH.

In one embodiment, —R^(A4) is independently —S-Q^(A4S).

The Group —R^(B3)

In one embodiment, —R^(B3) is independently —H or -Q^(B3).

In one embodiment, —R^(B3) is independently —H.

In one embodiment, —R^(B3) is independently -Q^(B3).

The Group —R^(B5)

In one embodiment, —R^(B5) is independently —H or -Q^(B5).

In one embodiment, —R^(B5) is independently —H.

In one embodiment, —R^(B5) is independently -Q^(B5).

The Group —R^(B6)

In one embodiment, —R^(B6) is independently —H or -Q^(B6).

In one embodiment, —R^(B6) is independently —H.

In one embodiment, —R^(B6) is independently -Q^(B6).

The Group -Q^(A4N)

In one embodiment, -Q^(A4N), if present, is independently -Q^(A4N1) or-Q^(A4N2).

In one embodiment, -Q^(A4N), if present, is independently -Q^(A4N1).

In one embodiment, -Q^(A4N), if present, is independently -Q^(A4N2).

The Group -Q^(A4N1)

In one embodiment, -Q^(A4N1), if present, is independently —NHR^(QN1) or—NR^(QN1) ₂.

In one embodiment, -Q^(A4N1), if present, is independently —NHR^(QN1).

In one embodiment, -Q^(A4N1), if present, is independently —NR^(QN1) ₂.

In one embodiment, each —R^(QN1), if present, is independently:

-   -   —R^(I1), —R^(I2), —R^(I3), —R^(I4), —R^(I5), —R^(I6), —R^(I7),        —R^(I8),    -   -L^(I)-R^(I4), -L^(I)-R^(I5), -L^(I)-R^(I6), -L^(I)-R^(I7), or        -L^(I)-R^(I8);

wherein:

-   -   each —R^(I1) is independently saturated aliphatic C₁₋₆alkyl;    -   each —R^(I2) is independently aliphatic C₂₋₆alkenyl;    -   each —R^(I3) is independently aliphatic C₂₋₆alkynyl;    -   each —R^(I4) is independently saturated C₃₋₆cycloalkyl;    -   each —R^(I5) is independently C₃₋₆cycloalkenyl;    -   each —R^(I6) is independently non-aromatic C₃₋₈heterocyclyl;    -   each —R^(I7) is independently C₆₋₁₀carboaryl;    -   each —R^(I8) is independently C₆₋₁₀heteroaryl;    -   each -L^(I)- is independently saturated aliphatic C₁₋₃alkylene;

and wherein:

-   -   each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkenyl, non-aromatic C₃₋₈heterocyclyl, C₆₋₁₀carboaryl,        C₆₋₁₀heteroaryl, and C₁₋₃alkylene is optionally substituted, for        example, with one or more substituents —R^(I9), wherein each        —R^(I9) is independently:    -   —F, —Cl, —Br, —I,    -   —R^(L1),    -   —CF₃, —OCF₃,    -   —OH, -L^(L)-OH, —O-L^(L)-OH,    -   —OR^(L1), -L^(L)-OR^(L1), —O-L^(L)-OR^(L1),    -   —SH, —SR^(L1),    -   —CN,    -   —NO₂,    -   —NH₂, —NHR^(L1), —NR^(L1) ₂, —NR^(L2)R^(L3),    -   -L^(L)-NH₂, -L^(L)-NHR^(L1), -L^(L)-NR^(L1) ₂,        -L^(L)-NR^(L2)R^(L3),    -   —O-L^(L)-NH₂, —O-L^(L)-NHR^(L1), —O-L^(L)-NR^(L1) ₂,        —O-L^(L)-NR^(L2)R^(L3),    -   —C(═O)OH, —C(═O)OR^(L1),    -   —C(═O)NH₂, —C(═O)NHR^(L1), —C(═O)NR^(L1) ₂, —C(═O)NR^(L2)R^(L3),    -   —NHC(═O)R^(L1), —NR^(L1)C(═O)R^(L1),    -   —NHC(═O)OR^(L1), —NR^(L1)C(═O)OR^(L1),    -   —OC(═O)NH₂, —OC(═O)NHR^(L1), —OC(═O)NR^(L1) ₂,        —OC(═O)NR^(L2)R^(L3),    -   —C(═O)R^(L1),    -   —NHC(═O)NH₂, —NHC(═O)NHR^(L1),    -   —NHC(═O)NR^(L1) ₂, —NHC(═O)NR^(L2)R^(L3),    -   —NR^(L1)C(═O)NH₂, —NR^(L1)C(═O)NHR^(L1),    -   —NR^(L1)C(═O)NR^(L1) ₂, —NR^(L1)C(═O)NR^(L2)R^(L3),    -   —NHS(═O)₂R^(L1), —NR^(L1)S(═O)₂R^(L1),    -   —S(═O)₂NH₂, —S(═O)₂NHR^(L1), —S(═O)₂NR^(L1) ₂,        —S(═O)₂NR^(L2)R^(L3),    -   —S(═O)R^(L1), —S(═O)₂R^(L1), —OS(═O)₂R^(L1), or —S(═O)₂OR^(L1);

wherein:

-   -   each -L^(L)- is independently saturated aliphatic C₁₋₆alkylene;    -   in each group —NR^(L2)R^(L3), R^(L2) and R^(L3), taken together        with the nitrogen atom to which they are attached, form a 4-,        5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring        heteroatom or exactly 2 ring heteroatoms, wherein one of said        exactly 2 ring heteroatoms is N, and the other of said exactly 2        ring heteroatoms is independently N or O;    -   each —R^(L1) is independently:        -   —R^(Z1), —R^(Z5), —R^(Z6), —R^(Z7), —R^(Z8),        -   -L^(Z)-R^(Z4), -L^(Z)-R^(Z6), -L^(Z)-R^(Z7), or            -L^(Z)-R^(Z8);    -   wherein:        -   each —R^(Z1) is independently saturated aliphatic C₁₋₆alkyl;        -   each —R^(Z4) is independently saturated C₃₋₆cycloalkyl;        -   each —R^(Z6) is independently non-aromatic C₃₋₈heterocyclyl;        -   each —R^(Z7) is independently C₆₋₁₀carboaryl;        -   each —R^(Z8) is independently C₆₋₁₀heteroaryl;        -   each -L^(Z)- is independently saturated aliphatic            C₁₋₃alkylene;    -   and wherein:    -   each C₁₋₆alkyl, C₃₋₆cycloalkyl, non-aromatic C₃₋₈heterocyclyl,        C₆₋₁₀carboaryl, C₅₋₁₀heteroaryl, and C₁₋₃alkylene is optionally        substituted, for example, with one or more substituents —R^(Z9),        wherein each —R^(Z9) is independently:        -   —F, —Cl, —Br, —I,        -   —R^(ZZ1),        -   —CF₃, —OCF₃,        -   —OH, -L^(ZZ)-OH,        -   —OR^(ZZ1), -L^(ZZ)-OR^(ZZ1),        -   —SH, —SR^(ZZ1),        -   —CN,        -   —NO₂,        -   —NH₂, —NHR^(ZZ1), —NR^(ZZ1) ₂, —NR^(ZZ2)R^(ZZ3),        -   -L^(ZZ)-NH₂, -L^(ZZ)-NHR^(ZZ1), -L^(ZZ)-NR^(ZZ1) ₂,            -L^(ZZ)-NR^(ZZ2)R^(ZZ3),        -   —C(═O)OH, —C(═O)OR^(ZZ1),        -   —C(═O)NH₂, —C(═O)NHR^(ZZ1), —C(═O)NR^(ZZ1) ₂, or            —C(═O)NR^(ZZ2)R^(ZZ3);    -   wherein:    -   each —R^(ZZ1) is independently saturated aliphatic C₁₋₄alkyl,        phenyl, or benzyl;    -   each -L^(ZZ)- is independently saturated aliphatic C₁₋₅alkylene;        and    -   in each group —NR^(ZZ2)R^(ZZ3), R^(ZZ2) and R^(ZZ3), taken        together with the nitrogen atom to which they are attached, form        a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1        ring heteroatom or exactly 2 ring heteroatoms, wherein one of        said exactly 2 ring heteroatoms is N, and the other of said        exactly 2 ring heteroatoms is independently N or O.

In one embodiment, each —R^(QN1), if present, is independently:

-   -   —R^(I1), —R^(I4), —R^(I6), —R^(I7), —R^(I8),    -   -L^(I)-R^(I4), -L^(I)-R^(I6), -L^(I)-R^(I7), or -L^(I)-R^(I8).

In one embodiment, each —R^(QN1), if present, is independently:

-   -   —R^(I1), —R^(I4), —R^(I6), —R^(I8),    -   -L^(I)-R^(I4), -L^(I)-R^(I6), -L^(I)-R^(I7) or -L^(I)-R^(I8).

In one embodiment, each —R^(QN1), if present, is independently —R^(I1),—R^(I6), or -L^(I)-R^(I6).

In one embodiment, each —R^(QN1), if present, is independently —R^(I1).

In one embodiment, each —R^(QN1), if present, is independently —R^(I6).

In one embodiment, each —R^(QN1), if present, is independently-L^(I)-R^(I6).

In one embodiment, each —R^(QN1), if present, is independently —R^(I7)or -L^(I)-R^(I7).

In one embodiment, each —R^(QN1), if present, is independently —R^(I8)or -L^(I)-R^(I8).

In one embodiment, each —R^(I1), if present, is independently asaturated aliphatic C₁₋₅alkyl.

In one embodiment, each -L^(I)-, if present, is independently —CH₂— or—CH₂CH₂—.

In one embodiment, each -L^(I)-, if present, is independently —CH₂—.

In one embodiment, each —R^(I4)—, if present, is independentlycyclohexyl, and is optionally substituted.

In one embodiment, each —R^(I6), if present, is a C₃₋₈heterocyclylgroupthat is a 4-, 5-, 6-, or 7-membered non-aromatic monocyclic ring or a 7-or 8-membered non-aromatic bicyclic ring, said ring having exactly 1ring heteroatom or exactly 2 ring heteroatoms, wherein each of said ringheteroatoms is independently N, O, or S; and is optionally substituted.

In one embodiment, each —R^(I6), if present, is independentlyazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl,piperazinyl, morpholinyl, azepinyl, diazepinyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dioxanyl,3-aza-bicyclo[3.2.1]octanyl, 8-aza-bicyclo[3.2.1]octanyl,3,8-diaza-bicyclo[3.2.1]octanyl, 3-aza-bicyclo[3.1.1]heptanyl,6-aza-bicyclo[3.1.1]heptanyl, 3,6-diaza-bicyclo[3.1.1]heptanyl,2-azabicyclo[2.2.2]octanyl, 1-azabicyclo[2.2.1]heptanyl, quinuclidinyl,or 9-azabicyclo[3.3.1]nonanyl; and is optionally substituted.

For convenience, the structures of the following groups are illustrated:

In one embodiment, each —R^(I6), if present, is independentlypyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl, or 8-aza-bicyclo[3.2.1]octanyl, and is optionallysubstituted.

In one embodiment, each —R^(I6), if present, is independentlypyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, or8-aza-bicyclo[3.2.1]octanyl; and is optionally substituted.

In one embodiment, each —R^(I6), if present, is independentlypiperidinyl or 8-aza-bicyclo[3.2.1]octanyl; and is optionallysubstituted.

In one embodiment, each —R^(I6), if present, is independentlypiperidinyl; and is optionally substituted.

In one embodiment, each —R^(I6), if present, is independently8-aza-bicyclo[3.2.1]octanyl; and is optionally substituted.

In one embodiment, each —R^(I7), if present, is independently phenyl,and is optionally substituted.

In one embodiment, each —R^(I8), if present, is independentlyC₅₋₆heteroaryl, and is optionally substituted.

In one embodiment, each —R^(I8), if present, is independently furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, orpyridazinyl, and is optionally substituted.

In one embodiment, each —R^(I8), if present is independently pyridyl,and is optionally substituted.

In one embodiment, each —R^(I9), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(L1),    -   —CF₃, —OCF₃,    -   —OH, -L^(L)-OH,    -   —OR^(L1), -L^(L)-OR^(L1),    -   —CN,    -   —NH₂, —NHR^(L1), —NR^(L1) ₂, —NR^(L2)R^(L3),    -   -L^(L)-NH₂, -L^(L)-NHR^(L1), -L^(L)-NR^(L1) ₂,        -L^(L)-NR^(L2)R^(L3),    -   —O-L^(L)-NH₂, —O-L^(L)-NHR^(L1), —O-L^(L)-NR^(L1) ₂,        —O-L^(L)-NR^(L2)R^(L3),    -   —C(═O)OH, —C(═O)OR^(L1),    -   —C(═O)NH₂, —C(═O)NHR^(L1), —C(═O)NR^(L1) ₂, —C(═O)NR^(L2)R^(L3),    -   —NHC(═O)R^(L1), —NR^(L1)C(═O)R^(L1),    -   —NHC(═O)OR^(L1), —NR^(L1)C(═O)OR^(L1),    -   —OC(═O)NH₂, —OC(═O)NHR^(L1), —OC(═O)NR^(L1) ₂,        —OC(═O)NR^(L2)R^(L3),    -   —C(═O)R^(L1),    -   —S(═O)₂NH₂, —S(═O)₂NHR^(L1), —S(═O)₂NR^(L1) ₂,        —S(═O)₂NR^(L2)R^(L3),    -   —S(═O)R^(L1), —S(═O)₂R^(L1), or —S(═O)₂OR^(L1).

In one embodiment, each —R^(I9), if present, is independently:

-   -   —R^(L1),    -   —OH, —OR^(L1),    -   —NH₂, —NHR^(L1), —NR^(L1) ₂, —NR^(L2)R^(L3),    -   —C(═O)NH₂, —C(═O)NHR^(L1), —C(═O)NR^(L1) ₂, or        —C(═O)NR^(L2)R^(L3).

In one embodiment, each -L^(L)-, if present, is independently saturatedaliphatic C₁₋₃alkylene.

In one embodiment, each —NR^(L2)R^(L3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —NR^(L2)R^(L3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —R^(L1), if present, is independently:

-   -   —R^(Z1), —R^(Z4), —R^(Z7), —R^(Z8),    -   -L^(Z)-R^(Z4), -L^(Z)-R^(Z7), or -L^(Z)-R^(Z8).

In one embodiment, each —R^(L1), if present, is independently:

-   -   —R^(Z1), —R^(Z4), —R^(Z7),    -   -L^(Z)-R^(Z4), or -L^(Z)-R^(Z7).

In one embodiment, each —R^(L1), if present, is independently —R^(Z1),—R^(Z7), or -L^(Z)-R^(Z7).

In one embodiment, each —R^(L1), if present, is independently —R^(Z1).

In one embodiment, each -L^(Z)-, if present, is independently —CH₂—.

In one embodiment, each —R^(Z1), if present, is independently asaturated aliphatic C₁₋₃alkyl.

In one embodiment, each —R^(Z6), if present, is a C₃₋₈heterocyclylgroupthat is a 4-, 5-, 6-, or 7-membered non-aromatic monocyclic ring or a 7-or 8-membered non-aromatic bicyclic ring, said ring having exactly 1ring heteroatom or exactly 2 ring heteroatoms, wherein each of said ringheteroatoms is independently N, O, or S; and is optionally substituted.

In one embodiment, each —R^(Z6), if present, is independentlyindependently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl,tetrahydrofuranyl, tetrahydropyranyl, dioxanyl,8-aza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[3.2.1]octanyl,6-aza-bicyclo[3.1.1]heptanyl, or 3,6-diaza-bicyclo[3.1.1]heptanyl; andis optionally substituted.

In one embodiment, each —R^(Z6), if present, is independentlypyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,or tetrahydropyranyl; and is optionally substituted.

In one embodiment, each —R^(Z7), if present, is independently phenyl,and is optionally substituted.

In one embodiment, each —R^(Z8), if present, is independentlyC₅₋₆heteroaryl, and is optionally substituted.

In one embodiment, each —R^(Z8), if present, is independently furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, orpyridazinyl, and is optionally substituted.

In one embodiment, each —R^(Z9), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(ZZ1),    -   —CF₃, —OCF₃,    -   —OH, -L^(ZZ)-OH,    -   —OR^(ZZ1), -L^(ZZ)-OR^(ZZ1),    -   —NH₂, —NHR^(ZZ1), —NR^(ZZ1) ₂, —NR^(ZZ2)R^(ZZ3),    -   -L^(ZZ)-NH₂, -L^(ZZ)-NHR^(ZZ1), -L^(ZZ)-NR^(ZZ1) ₂,        -L^(ZZ)-NR^(ZZ2)R^(ZZ3),    -   —C(═O)OH, —C(═O)OR^(ZZ1),    -   —C(═O)NH₂, —C(═O)NHR^(ZZ1), —C(═O)NR^(ZZ1) ₂, or        —C(═O)NR^(ZZ2)R^(ZZ3).

In one embodiment, each -L^(ZZ), if present, is independently saturatedaliphatic C₁₋₃alkylene.

In one embodiment, each —R^(ZZ1), if present, is independentlyC₁₋₄alkyl.

In one embodiment, each —NR^(ZZ2)R^(ZZ3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —NR^(ZZ2)R^(ZZ3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —R^(Z9), if present, is independently —F, —Cl,—Br, —I, -Me, -Et, —CF₃, —OH, —CH₂OH, —CH₂CH₂OH, —OMe, —OEt, —CH₂OMe,—CH₂CH₂OMe, —OCF₃, —SMe, —CN, —NO₂, —NH₂, —NHMe, —NMe₂, —CH₂NH₂,—CH₂NHMe, —CH₂NMe₂, —CH₂CH₂NH₂, —CH₂CH₂NHMe, —CH₂CH₂NMe₂, —C(═O)OH,—C(═O)OMe, —C(═O)NH₂, —C(═O)NHMe, —C(═O)NMe₂, —C(═O)NHPh, —C(═O)N(Me)Ph,—C(═O)NHCH₂Ph, —C(═O)N(Me)CH₂Ph, —CH₂-Ph, or -Ph.

In one embodiment, -Q^(A4N1), if present, is independently selected fromgroups of the following formulae, wherein n1 is independently 1, 2, 3,or 4; n2 is independently 1, 2, 3, or 4: and n3 is independently 1 or 2:

In one embodiment, -Q^(A4N1), if present, is independently a group offormula (A4N1-A).

In one embodiment, -Q^(A4N1), if present, is independently a group offormula (A4N1-B).

In one embodiment, -Q^(A4N1), if present, is independently a group offormula (A4N1-C).

In one embodiment, -Q^(A4N1), if present, is independently selected fromgroups of the following formulae, wherein n4 is independently 1 or 2:

In one embodiment, -Q^(A4N1), if present, is independently selected fromgroups of the following formulae, wherein n4 is independently 1 or 2:

In one embodiment, -Q^(A4N1), if present, is independently a group offormula (A4N1-D).

In one embodiment, -Q^(A4N1), if present, is independently a group offormula (A4N1-E).

In one embodiment, -Q^(A4N1), if present, is independently a group offormula (A4N1-F).

In one embodiment, -Q^(A4N1), if present, is independently a group offormula (A4N1-G).

In one embodiment, -Q^(A4N1), if present, is independently a group offormula (A4N1-H).

In one embodiment, -Q^(A4N1), if present, is independently a group offormula (A4N1-I).

In one embodiment, -Q^(A4N1), if present, is independently a group offormula (A4N1-J).

In one embodiment, -Q^(A4N1), if present, is independently a group offormula (A4N1-K).

In one embodiment, n4 is independently 1.

In one embodiment, —R^(NN1) is independently —H or saturated aliphaticC₁₋₄alkyl.

In one embodiment, —R^(NN1) is independently —H or -Me.

In one embodiment, —R^(NN1) is independently saturated aliphaticC₁₋₄alkyl.

In one embodiment, —R^(NN1) is independently -Me.

In one embodiment, —R^(NN1) is independently —H.

In one embodiment, each —R^(NN2) is independently —H, saturatedaliphatic C₁₋₄alkyl, phenyl, or benzyl; or, the group —NR^(NN2)R^(NN2)is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino,piperidino, piperazino, morpholino, azepino, or diazepino, and isoptionally substituted, for example, with one or more groups selectedfrom C₁₋₃alkyl and —CF₃.

In one embodiment, each —R^(NN2) is independently —H, saturatedaliphatic C₁₋₄alkyl, phenyl, or benzyl; or, the group —NR^(NN2)R^(NN2)is independently pyrrolidino, piperidino, piperazino, ormorpholino, andis optionally substituted, for example, with one or more groups selectedfrom C₁₋₃alkyl and —CF₃.

In one embodiment, each —R^(NN2) is independently —H, saturatedaliphatic C₁₋₄alkyl, phenyl, or benzyl.

In one embodiment, each —R^(NN2) is independently —H or saturatedaliphatic C₁₋₄alkyl.

In one embodiment, each —R^(NN2) is independently —H or -Me.

In one embodiment, each —R^(NN2) is independently -H.

In one embodiment, —R^(NN3), if present, is independently —H orsaturated aliphatic C₁₋₄alkyl.

In one embodiment, —R^(NN3), if present, is independently —H or -Me.

In one embodiment, —R^(NN3), if present, is independently —H.

In one embodiment, —R^(NN4), if present, is independently —H, saturatedaliphatic C₁₋₄alkyl, phenyl, or benzyl.

In one embodiment, —R^(NN4), if present, is independently —H orsaturated aliphatic C₁₋₄alkyl.

In one embodiment, —R^(NN4), if present, is independently —H or -Me.

In one embodiment, —R^(NN4), if present, is independently —H.

In one embodiment, —R^(NN4), if present, is independently -Me.

In one embodiment, -Q^(A4N1), if present, is independently selected fromthose substituents exemplified under the heading “Some PreferredEmbodiments.”

The Group -Q^(A4N2)

In one embodiment, -Q^(A4N2), if present, is independently—NR^(QN2)R^(QN3).

In one embodiment, in the group —NR^(QN2)R^(QN3), if present, R^(QN2)and R^(QN3), taken together with the nitrogen atom to which they areattached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring havingexactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one ofsaid exactly 2 ring heteroatoms is N, and the other of said exactly 2ring heteroatoms is independently N or O.

In one embodiment, —NR^(QN2)R^(QN3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted.

In one embodiment, —NR^(QN2)R^(QN3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted.

In one embodiment, —NR^(QN2)R^(QN3), if present, is independentlypiperidino, piperazino, or morpholino, and is optionally substituted.

In one embodiment, —NR^(QN2)R^(QN3) is optionally substituted, forexample, with one or more substituents —R^(QNR), wherein each —R^(QNR)is independently:

-   -   —F,    -   —R^(AA1),    -   —CF₃,    -   —OH, -L^(AA)-OH, —O-L^(AA)-OH,    -   —OR^(AA1), -L^(AA)-OR^(AA1), —O-L^(AA)-OR^(AA1),    -   —SH, —SR^(AA1),    -   —CN,    -   —NH₂, —NHR^(AA1), —NR^(AA1) ₂, —NR^(AA2)R^(AA3),    -   -L^(AA)-NH₂, -L^(AA)-NHR^(AA1), -L^(AA)-NR^(AA1) ₂,        -L^(AA)-NR^(AA2)R^(AA3),    -   —O-L^(AA)-NH₂, —O-L^(AA)-NHR^(AA1), —O-L^(AA)-NR^(AA1) ₂,        —O-L^(AA)-NR^(AA2)R^(AA3),    -   —C(═O)OH, —C(═O)OR^(AA1),    -   —C(═O)NH₂, —C(═O)NHR^(AA1), —C(═O)NR^(AA1) ₂,        —C(═O)NR^(AA2)R^(AA3),    -   —NHC(═O)R^(AA1), —NR^(AA1)C(═O)R^(AA1),    -   —NHC(═O)OR^(AA1), —NR^(AA1)C(═O)OR^(AA1),    -   —OC(═O)NH₂, —OC(═O)NHR^(AA1), —OC(═O)NR^(AA1) ₂,        —OC(═O)NR^(AA2)R^(AA3),    -   —C(═O)R^(AA1),    -   —NHC(═O)NH₂, —NHC(═O)NHR^(AA1),    -   —NHC(═O)NR^(AA1) ₂, —NHC(═O)NR^(AA2)R^(AA3),    -   —NR^(AA1)C(═O)NH₂, —NR^(AA1)C(═O)NHR^(AA1) ,    -   —NR^(AA1)C(═O)NR^(AA1) ₂, —NR^(AA1)C(═O)NR^(AA2)R^(AA3),    -   —NHS(═O)₂R^(AA1), —NR^(AA1)S(═O)₂R^(AA1),    -   —S(═O)₂NH₂, —S(═O)₂NHR^(AA1), —S(═O)₂NR^(AA1) ₂,        —S(═O)₂NR^(AA2)R^(AA3),    -   —S(═O)R^(AA1), —S(═O)₂R^(AA1), —OS(═O)₂R^(AA1), or        —S(═O)₂OR^(AA1);

wherein:

-   -   each -L^(AA)- is independently saturated aliphatic C₁₋₆alkylene;    -   in each group —NR^(AA2)R^(AA3), R^(AA2) and R^(AA3), taken        together with the nitrogen atom to which they are attached, form        a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1        ring heteroatom or exactly 2 ring heteroatoms, wherein one of        said exactly 2 ring heteroatoms is N, and the other of said        exactly 2 ring heteroatoms is independently N or O;    -   each —R^(AA1) is independently:        -   —R^(BB1), —R^(BB4), —R^(BB6), —R^(BB7), —R^(BB8),        -   -L^(BB)-R^(BB4), -L^(BB)-R^(BB6), -L^(BB)-R^(BB7), or            -L^(BB)-R^(BB8);    -   wherein:        -   each —R^(BB1) is independently saturated aliphatic            C₁₋₆alkyl;        -   each —R^(BB4) is independently saturated C₃₋₆cycloalkyl;        -   each —R^(BB6) is independently non-aromatic            C₃₋₈heterocyclyl;        -   each —R^(BB7) is independently C₆₋₁₀carboaryl;        -   each —R^(BB8) is independently C₅₋₁₀heteroaryl;        -   each -L^(BB)- is independently saturated aliphatic            C₁₋₃alkylene;    -   and wherein:    -   each C₁₋₆alkyl, C₃₋₆cycloalkyl, non-aromatic C₃₋₆heterocyclyl,        C₆₋₁₀carboaryl, C₅₋₁₀heteroaryl, and C₁₋₃alkylene is optionally        substituted, for example, with one or more substituents        —R^(BB9), wherein each —R^(BB9) is independently:        -   —F, —Cl, —Br, —I,        -   R^(CC1),        -   —CF₃, —OCF₃,        -   —OH, -L^(CC)-OH,        -   —OR^(CC1), -L^(CC)-OR^(CC1),        -   —SH, —SR^(CC1),        -   —CN,        -   —NO₂,        -   —NH₂, —NHR^(CC1), —NR^(CC1) ₂, —NR^(CC2)R^(CC3),        -   -L^(CC)-NH₂, -L^(CC)-NHR^(CC1), -L^(CC)-NR^(CC1) ₂,            -L^(CC)-NR^(CC2)R^(CC3),        -   —C(═O)OH, —C(═O)OR^(CC1),        -   —C(═O)NH₂, —C(═O)NHR^(CC1), —C(═O)NR^(CC1) ₂, or            —C(═O)NR^(CC2)R^(CC3);    -   wherein:    -   each —R^(CC1) is independently saturated aliphatic C₁₋₄alkyl,        phenyl, or benzyl;    -   each -L^(CC)- is independently saturated aliphatic C₁₋₅alkylene;        and    -   in each group —NR^(CC2)R^(CC3), R^(CC2) and R^(CC3), taken        together with the nitrogen atom to which they are attached, form        a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1        ring heteroatom or exactly 2 ring heteroatoms, wherein one of        said exactly 2 ring heteroatoms is N, and the other of said        exactly 2 ring heteroatoms is independently N or O.

In one embodiment, each —R^(QNR), if present, is independently:

-   -   —F,    -   —R^(AA1),    -   —CF₃,    -   —OH, -L^(AA)-OH, —O-L^(AA)-OH,    -   —OR^(AA1), -L^(AA)-OR^(AA1), —O-L^(AA)-OR^(AA1),    -   —CN,    -   —NH₂, —NHR^(AA1), —NR^(AA1) ₂, —NR^(AA2)R^(AA3),    -   -L^(AA)-NH₂, -L^(AA)-NHR^(AA1), -L^(AA)-NR^(AA1) ₂,        -L^(AA)-NR^(AA2)R^(AA3),    -   —O-L^(AA)-NH₂, —O-L^(AA)-NHR^(AA1), —O-L^(AA)-NR^(AA1) ₂,        —O-L^(AA)-NR^(AA2)R^(AA3),    -   —C(═O)OH, —C(═O)OR^(AA1),    -   —C(═O)NH₂, —C(═O)NHR^(AA1), —C(═O)NR^(AA1) ₂,        —C(═O)NR^(AA2)R^(AA3),    -   —NHC(═O)R^(AA1), —NR^(AA1)C(═O)R^(AA1),    -   —NHS(═O)₂R^(AA1), —NR^(AA1)S(═O)₂R^(AA1),    -   —S(═O)₂NH₂, —S(═O)₂NHR^(AA1), —S(═O)₂NR^(AA1) ₂,        —S(═O)₂NR^(AA2)R^(AA3),    -   —S(═O)R^(AA1), or —S(═O)₂R^(AA1).

In one embodiment, each —R^(QNR), if present, is independently:

-   -   —R^(AA1),    -   —NH₂, —NHR^(AA1), —NR^(AA1) ₂, —NR^(AA2)R^(AA3),    -   -L^(AA)-NH₂, -L^(AA)-NHR^(AA1), -L^(AA)-NR^(AA1) ₂, or        -L^(AA)-NR^(AA2)R^(AA3),

In one embodiment, each —R^(QNR), if present, is independently —R^(AA1),—NH₂, or -L^(AA)-NH₂.

In one embodiment, each —R^(QNR), if present, is independently —NH₂ or-L^(AA)-NH₂.

In one embodiment, each -L^(AA)-, if present, is independently saturatedaliphatic C₁₋₃alkylene.

In one embodiment, each -L^(AA)-, if present, is independently —CH₂— or—CH₂CH₂—.

In one embodiment, each -L^(AA)-, if present, is independently —CH₂—.

In one embodiment, each —NR^(AA2)R^(AA3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted, for example, with one or more groups selected fromC1-3alkyl and —CF₃.

In one embodiment, each —NR^(AA2)R^(AA3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —R^(AA1), if present, is independently:

-   -   —R^(BB1), —R^(BB4), —R^(BB7), —R^(BB8),    -   -L^(BB)-R^(BB4), -L^(BB)-R^(BB7), or -L^(BB)-R^(BB8).

In one embodiment, each —R^(AA1), if present, is independently:

-   -   —R^(BB1), —R^(BB4), —R^(BB7),    -   -L^(BB)-R^(BB4), or -L^(BB)-R^(BB7).

In one embodiment, each —R^(AA1), if present, is independently —R^(BB1),—R^(BB7), or -L^(BB)-R^(BB7).

In one embodiment, each —R^(AA1), if present, is independently —R^(BB1).

In one embodiment, each —R^(AA1), if present, is independently-L^(BB)-R^(BB7).

In one embodiment, each -L^(BB)-, if present, is independently —CH₂—.

In one embodiment, each —R^(BB1), if present, is independently asaturated aliphatic C₁₋₃alkyl.

In one embodiment, each —R^(BB6), if present, is a C₃₋₈heterocyclylgroupthat is a 4-, 5-, 6-, or 7-membered non-aromatic monocyclic ring, saidring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms,wherein each of said ring heteroatoms is independently N, O, or S; andis optionally substituted.

In one embodiment, each —R^(BB6), if present, is independentlyindependently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl,tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and is optionallysubstituted.

In one embodiment, each —R^(BB6), if present, is independentlypyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,or tetrahydropyranyl, and is optionally substituted.

In one embodiment, each —R^(BB7), if present, is independently phenyl,and is optionally substituted.

In one embodiment, each —R^(BB8), if present, is independentlyC₅₋₆heteroaryl, and is optionally substituted.

In one embodiment, each —R^(BB8), if present, is independently furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, orpyridazinyl, and is optionally substituted.

In one embodiment, each —R^(BB9), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(CC1),    -   —CF₃, —OCF₃,    -   —OH, -L^(CC)-OH,    -   —OR^(CC1), -L^(CC)-OR^(CC1),    -   —NH₂, —NHR^(CC1), —NR^(CC1) ₂, —NR^(CC2)R^(CC3),    -   -L^(CC)-NH₂, -L^(CC)-NHR^(CC1), -L^(CC)-NR^(CC1) ₂,        -L^(CC)-NR^(CC2)R^(CC3),    -   —C(═O)OH, —C(═O)OR^(CC1),    -   —C(═O)NH₂, —C(═O)NHR^(CC1), —C(═O)NR^(CC1) ₂, or        —C(═O)NR^(CC2)R^(CC3).

In one embodiment, each —R^(BB9), if present, is independently:

-   -   —R^(CC1),    -   —NH₂, —NHR^(CC1), —NR^(CC1) ₂, or —NR^(CC2)R^(CC3).

In one embodiment, each -L^(CC), if present, is independently saturatedaliphatic C₁₋₃alkylene.

In one embodiment, each —R^(CC1), if present, is independentlyC₁₋₄alkyl.

In one embodiment, each —R^(CC1), if present, is independently phenyl.

In one embodiment, each —NR^(CC2)R^(CC3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —NR^(CC2)R^(CC3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —R^(BB9), if present, is independently —F, —Cl,—Br, —I, -Me, -Et, —CF₃, —OH, —CH₂OH, —CH₂CH₂OH, —OMe, —OEt, —CH₂OMe,—CH₂CH₂OMe, —OCF₃, —SMe, —CN, —NO₂, —NH₂, —NHMe, —NMe₂, —CH₂NH₂,—CH₂CH₂NH₂, —O—CH₂CH₂—NH₂, —C(═O)OH, —C(═O)OMe, —C(═O)NH₂, —C(═O)NHMe,—C(═O)NMe₂, —SO₂NH₂, —SO₂NHMe, —SO₂NMe₂, —SO₂Me, —CH₂-Ph, or -Ph.

In one embodiment, -Q^(A4N2), if present, is independently selected fromgroups of the following formulae, wherein m1 is independently 1 or 2,and each —R^(MM1) is independently —H or saturated aliphatic C₁₋₄alkyl:

In one embodiment, -Q^(A4N2), if present, is independently a group offormula (A4N2-A).

In one embodiment, -Q^(A4N2), if present, is independently a group offormula (A4N2-B).

In one embodiment, each —R^(MM1) is independently —H or -Me.

In one embodiment, each —R^(MM1) is independently —H.

In one embodiment, -Q^(A4N2) if present, is independently the followinggroup, wherein each —R^(MM2) is independently —H or saturated aliphaticC₁₋₄alkyl:

In one embodiment, each —R^(MM2) is independently —H or -Me.

In one embodiment, each —R^(MM2) is independently —H.

In one embodiment, -Q^(A4N2), if present, is independently selected fromthose substituents exemplified under the heading “Some PreferredEmbodiments.”

The group —Q^(A4O)

In one embodiment, -Q^(A4O), if present, is independently —R^(C1),wherein —R^(C1) is independently:

-   -   —R^(D1), —R^(D2), —R^(D3), —R^(D4), —R^(D5), —R^(D6), —R^(D7),        —R^(D8),    -   -L^(D)-R^(D4), -L^(D)-R^(D5), -L^(D)-R^(D6), -L^(D)-R^(D7), or        -L^(D)-R^(D8);    -   wherein:    -   each —R^(D1) is independently saturated aliphatic C₁₋₆alkyl;    -   each —R^(D2) is independently aliphatic C₂₋₆alkenyl;    -   each —R^(D3) is independently aliphatic C₂₋₆alkynyl;    -   each —R^(D4) is independently saturated C₃₋₆cycloalkyl;    -   each —R^(D5) is independently C₃₋₆cycloalkenyl;    -   each —R^(D6) is independently non-aromatic C₃₋₈heterocyclyl;    -   each —R^(D7) is independently C₆₋₁₀carboaryl;    -   each —R^(D8) is independently C₅₋₁₀heteroaryl;    -   each -L^(D)- is independently saturated aliphatic C₁₋₃alkylene;    -   and wherein:    -   each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkenyl, non-aromatic C₃₋₈heterocyclyl, C₆₋₁₀carboaryl,        C₅₋₁₀heteroaryl, and C₁₋₃alkylene is optionally substituted, for        example, with one or more substituents —R^(D9), wherein each        —R^(D9) is independently:    -   —F, —C1, —Br, —I,    -   —R^(E1),    -   —CF₃, —OCF₃,    -   —OH, -L^(E)-OH, —O-L^(E)-OH,    -   —OR^(E1), -L^(E)-OR^(E1), —O-L^(E)-OR^(E1),    -   —SH, —SR^(E1),    -   —CN,    -   —NO₂,    -   —NH₂, —NHR^(E1), —NR^(E1) ₂, —NR^(E2)R^(E3),    -   -L^(E)-NH₂, -L^(E)-NHR^(E1), -L^(E)-NR^(E1) ₂,        -L^(E)-NR^(E2)R^(E3),    -   —O-L^(E)-NH₂, —O-L^(E)-NHR^(E1), —O-L^(E)-NR^(E1) ₂,        —O-L^(E)-NR^(E2)R^(E3),    -   —C(═O)OH, —C(═O)OR^(E1),    -   —C(═O)NH₂, —C(═O)NHR^(E1), —C(═O)NR^(E1) ₂, or        —C(═O)NR^(E2)R^(E3);    -   wherein:    -   each —R^(E1) is independently saturated aliphatic C₁₋₄alkyl,        phenyl, or benzyl;    -   each -L^(E)- is independently saturated aliphatic C₁₋₅alkylene;        and    -   in each group —NR^(E2)R^(E3), R^(E2) and R^(E3), taken together        with the nitrogen atom to which they are attached, form a 4-,        5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring        heteroatom or exactly 2 ring heteroatoms, wherein one of said        exactly 2 ring heteroatoms is N, and the other of said exactly 2        ring heteroatoms is independently N or O.

In one embodiment, —R^(C1), if present, is independently:

-   -   —R^(D1), —R^(D4), —R^(D6), —R^(D7), —R^(D8),    -   -L^(D)-R^(D4), -L^(D)-R^(D6), -L^(D)-R^(D7), or -L^(D)-R^(D8).

In one embodiment, —R^(C1), if present, is independently:

—R^(D1), —R^(D6), —R^(D7), —R^(D8),

-   -   -L^(D)-R^(D6), -L^(D)-R^(D7), or -L^(D)-R^(D8).

In one embodiment, —R^(C1), if present, is independently —R^(D6) or-L^(D)-R^(D6).

In one embodiment, —R^(C1), if present, is independently —R^(D6).

In one embodiment, —R^(C1), if present, is independently -L^(D)-R^(D6).

In one embodiment, each -L^(D)-, if present, is independently —CH₂— or—CH₂CH₂—.

In one embodiment, each -L^(D)-, if present, is independently —CH₂—.

In one embodiment, each —R^(D1), if present, is independently asaturated aliphatic C₁₋₃alkyl.

In one embodiment, each —R^(D6), if present, is a C₃₋₈heterocyclyl groupthat is a 4-, 5-, 6-, or 7-membered non-aromatic monocyclic ring or a 7-or 8-membered non-aromatic bicyclic ring, said ring having exactly 1ring heteroatom or exactly 2 ring heteroatoms, wherein each of said ringheteroatoms is independently N, O, or S; and is optionally substituted.

In one embodiment, each —R^(D6), if present, is independentlyazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl,piperazinyl, morpholinyl, azepinyl, diazepinyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dioxanyl,3-aza-bicyclo[3.2.1]octanyl, 8-aza-bicyclo[3.2.1]octanyl,3,8-diaza-bicyclo[3.2.1]octanyl, 3-aza-bicyclo[3.1.1]heptanyl,6-aza-bicyclo[3.1.1]heptanyl, 3,6-diaza-bicyclo[3.1.1]heptanyl,2-azabicyclo[2.2.2]octanyl, 1-azabicyclo[2.2.1]heptanyl, quinuclidinyl,or 9-azabicyclo[3.3.1]nonanyl, and is optionally substituted.

In one embodiment, each —R^(D6), if present, is independentlypyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,or tetrahydropyranyl, and is optionally substituted.

In one embodiment, each —R^(D7), if present, is independently phenyl,and is optionally substituted.

In one embodiment, each —R^(D8), if present, is independentlyC₅₋₆heteroaryl, and is optionally substituted.

In one embodiment, each 13 R^(D8), if present, is independently furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, orpyridazinyl, and is optionally substituted.

In one embodiment, each —R^(D8), if present is independently imidazolyl,pyrazolyl, triazolyl, pyridyl, pyrimidinyl, and is optionally subsituted

In one embodiment, each —R^(D8), if present, is independentlyC₉₋₁₀heteroaryl, and is optionally substituted.

In one embodiment, each —R^(D6), if present, is independently:

-   -   —F, —C1, —Br, —I,    -   —R^(E1),    -   —CF₃, —OCF₃,    -   —OH, -L^(E)-OH, —O-L^(E)-OH,    -   —OR^(E1), -L^(E)-OR^(E1), —O-L^(E)-OR^(E1),    -   —NH₂, —NHR^(E1), —NR^(E1) ₂, —NR^(E2)R^(E3),    -   -L^(E)-NH₂, -L^(E)-NHR^(E1), -L^(E)-NR^(E1) ₂,        -L^(E)-NR^(E2)R^(E3),    -   —O-L^(E)-NH₂, —O-L^(E)-NHR^(E1), —O-L^(E)-NR^(E1) ₂,        —O-L^(E)-NR^(E2)R^(E3),    -   —C(═O)OH, —C(═O)OR^(E1),    -   —C(═O)NH₂, —C(═O)NHR^(E1), —C(═O)NR^(E1) ₂, or        —C(═O)NR^(E2)R^(E3);

In one embodiment, each -L^(E)-, if present, is independently saturatedaliphatic C₁₋₃alkylene.

In one embodiment, each —R^(E1), if present, is independently C₁₋₄alkyl.

In one embodiment, each —NR^(E2)R^(E3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —NR^(E2)R^(E3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —R^(D9), if present, is independently —F, —C1,—Br, —I, -Me, -Et, —CF₃, —OH, —CH₂CH₂OH, —O—CH₂CH₂OH, —OMe, —OEt,—CH₂CH₂OMe, —O—CH₂CH₂OMe, —OCF₃, —SMe, —CN, —NO₂, —NH₂, —NHMe, —NMe₂,—CH₂CH₂NH₂, —CH₂CH₂NHMe, —CH₂CH₂NMe₂, —CH₂-(morpholino),—O—CH₂CH₂-(morpholino), —O—CH₂CH₂—NH₂, —C(═O)OH, —C(═O)OMe, —C(═O)NH₂,—C(═O)NHMe, —C(═O)NMe₂, —SO₂NH₂, —SO₂NHMe, —SO₂NMe₂, —SO₂Me, —CH₂-Ph, or-Ph.

In one embodiment, each -Q^(A4O), if present, is independently selectedfrom those substituents exemplified under the heading “Some PreferredEmbodiments.”

The Group -Q^(A4S)

In one embodiment, -Q^(A4S), if present, is independently —R^(F1),wherein —R^(F1) is independently:

-   -   —R^(G1), —R^(G2), —R^(G3), —R^(G4), —R^(G5), —R^(G6), —R^(G7),        —R^(G8),    -   -L^(G)-R^(G4), -L^(G)-R^(G5), —L^(G)-R^(G6), -L^(G)-R^(G7), or        -L^(G)-R^(G8);    -   wherein:    -   each —R^(G1) is independently saturated aliphatic C₁₋₆alkyl;    -   each —R^(G2) is independently aliphatic C₂₋₆alkenyl;    -   each —R^(G3) is independently aliphatic C₂₋₆alkynyl;    -   each —R^(G4) is independently saturated C₃₋₆cycloalkyl;    -   each —R^(G5) is independently C₃₋₆cycloalkenyl;    -   each —R^(G6) is independently non-aromatic C₃₋₈heterocyclyl;    -   each —R^(G7) is independently C₆₋₁₀carboaryl;    -   each —R^(G8) is independently C₅₋₁₀heteroaryl;    -   each -L^(G)- is independently saturated aliphatic C₁₋₃alkylene;    -   and wherein:    -   each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkenyl, non-aromatic C₃₋₆heterocyclyl, C₆₋₁₀carboaryl,        C₅₋₁₀heteroaryl, and C₁₋₃alkylene is optionally substituted, for        example, with one or more substituents —R^(G9), wherein each        —R^(G9) is independently:    -   —F, —C1, —Br, —I,    -   —R^(H1),    -   —CF₃, —OCF₃,    -   —OH, -L^(H)-OH, —O-L^(H)-OH,    -   —OR^(H1), -L^(H)-OR^(H1), —O-L^(H)-OR^(H1),    -   —SH, —SR^(H1),    -   —CN,    -   —NO₂,    -   —NH₂, —NHR^(H1), —NR^(H1) ₂, —NR^(H2)R^(H3),    -   -L^(H)-NH₂, -L^(H)-NHR^(H1), -L^(H)-NR^(H1) ₂,        -L^(H)-NR^(H2)R^(H3),    -   —O-L^(H)-NH₂, —O-L^(H)-NHR^(H1), —O-L^(H)-NR^(H1) ₂,        —O-L^(H)-NR^(H2)R^(H3),    -   —C(═O)OH, —C(═O)OR^(H1),    -   —C(═O)NH₂, —C(═O)NHR^(H1), —C(═O)NR^(H1) ₂, or        —C(═O)NR^(H2)R^(H3);    -   wherein:    -   each —R^(H1) is independently saturated aliphatic C₁₋₄alkyl,        phenyl, or benzyl;    -   each -L^(H)- is independently saturated aliphatic C₁₋₅alkylene;        and    -   in each group —NR^(H2)R^(H3), R^(H2) and R^(H3), taken together        with the nitrogen atom to which they are attached, form a 4-,        5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring        heteroatom or exactly 2 ring heteroatoms, wherein one of said        exactly 2 ring heteroatoms is N, and the other of said exactly 2        ring heteroatoms is independently N or O.

In one embodiment, —R^(F1), if present, is independently:

-   -   —R^(G1), —R^(G4), —R^(G6), —R^(G7), —R^(G8),    -   -L^(G)-R^(G4), -L^(G)-R^(G6), -L^(G)-R^(G7), or -L^(G)—R^(G8).

In one embodiment, R^(F1), if present, is independently:

-   -   —R^(G1), —R^(G6), —R^(G7), —R^(G8),    -   -L^(G)-R^(G6), -L^(G)-R^(G7), -L^(G)-R^(G8).

In one embodiment, —R^(F1), if present, is independently —R^(G6) or-L^(G)-R^(G6).

In one embodiment, —R^(F1), if present, is independently —R^(G6).

In one embodiment, —R^(F1), if present, is independently -L^(G)-R^(G6).

In one embodiment, each -L^(G)-, if present, is independently —CH₂— or—CH₂CH₂—.

In one embodiment, each -L^(G)-, if present, is independently —CH₂—.

In one embodiment, each —R^(G1), if present, is independently asaturated aliphatic C₁₋₃alkyl.

In one embodiment, each —R^(G6), if present, is a C₃₋₈heterocyclylgroupthat is a 4-, 5-, 6-, or 7-membered non-aromatic monocyclic ring or a 7-or 8-membered non-aromatic bicyclic ring, said ring having exactly 1ring heteroatom or exactly 2 ring heteroatoms, wherein each of said ringheteroatoms is independently N, O, or S; and is optionally substituted.

In one embodiment, each —R^(G6), if present, is independently isindependently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dioxanyl,3-aza-bicyclo[3.2.1]octanyl, 8-aza-bicyclo[3.2.1]octanyl,3,8-diaza-bicyclo[3.2.1]octanyl, 3-aza-bicyclo[3.1.1]heptanyl,6-aza-bicyclo[3.1.1]heptanyl, 3,6-diaza-bicyclo[3.1.1]heptanyl,2-azabicyclo[2.2.2]octanyl, 1-azabicyclo[2.2.1]heptanyl, quinuclidinyl,or 9-azabicyclo[3.3.1]nonanyl, and is optionally substituted.

In one embodiment, each —R^(G6), if present, is independentlypyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,or tetrahydropyranyl, and is optionally substituted.

In one embodiment, each —R^(G7), if present, is independently phenyl,and is optionally substituted.

In one embodiment, each —R^(G8), if present, is independentlyC₅₋₆heteroaryl, and is optionally substituted.

In one embodiment, each —R^(G8), if present, is independently furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, orpyridazinyl, and is optionally substituted.

In one embodiment, each —R^(G8), if present, is independentlyimidazolyl, pyrazolyl, triazolyl, pyridyl, or pyrimidinyl, and isoptionally substituted.

In one embodiment, each —R^(G8), if present, is independentlyC₉₋₁₀heteroaryl, and is optionally substituted.

In one embodiment, each —R^(G9), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(H1),    -   —CF₃, —OCF₃,    -   —OH, -L^(H)-OH, —O-L^(H)-OH,    -   —OR^(H1), -L^(H)-OR^(H1), —O-L^(H)-OR^(H1),    -   —NH₂, —NHR^(H1), —NR^(H1) ₂, —NR^(H2)R^(H3),    -   -L^(H)-NH₂, -L^(H)-NHR^(H1), -L^(H)-NR^(H1) ₂,        -L^(H)-NR^(H2)R^(H3),    -   —O-L^(H)-NH₂, —O-L^(H)-NHR^(H1), —O-L^(H)-NR^(H1) ₂,        —O-L^(H)-NR^(H2)R^(H3),    -   —C(═O)OH, —C(═O)OR^(H1),    -   —C(═O)NH₂, —C(═O)NHR^(H1), —C(═O)NR^(H1) ₂, or        —C(═O)NR^(H2)R^(H3).

In one embodiment, each -L^(H)-, if present, is independently saturatedaliphatic C₁₋₃alkylene.

In one embodiment, each —R^(H1), if present, is independently C₁₋₄alkyl.

In one embodiment, each —NR^(H2)R^(H3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —NR^(H2)R^(H3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —R^(G9), if present, is independently —F, —C1,—Br, —I, -Me, -Et, —CF₃, —OH, —CH₂CH₂OH, —O—CH₂CH₂OH, —OMe, —OEt,—CH₂CH₂OMe, —O—CH₂CH₂OMe, —OCF₃, —SMe, —CN, —NO₂, —NH₂, —NHMe, —NMe₂,—CH₂CH₂NH₂, —CH₂CH₂NHMe, —CH₂CH₂NMe₂, —CH₂-(morpholino),—O—CH₂CH₂-(morpholino), —O—CH₂CH₂—NH₂, —C(═O)OH, —C(═O)OMe, —C(═O)NH₂,—C(═O)NHMe, —C(═O)NMe₂, —SO₂NH₂, —SO₂NHMe, —SO₂NMe₂, —SO₂Me, —CH₂-Ph, or-Ph.

In one embodiment, -Q^(A4S), if present, is independently selected fromthose substituents exemplified under the heading “Some PreferredEmbodiments.”

The Group Q^(A5)

In one embodiment, Q^(A5), if present, is independently:

-   -   —F, —C1, —Br, —I,    -   —R^(J1),    -   —CF₃, —OCF₃,    -   —OH, -L^(J)-OH, —O-L^(J)-OH,    -   —OR^(J1), -L^(J)-OR^(J1), —O-L^(J)-OR^(J1),    -   —SH, —SR^(J1),    -   —CN,    -   —NO₂,    -   —NH₂, —NHR^(J1), —NR^(J1) ₂, —NR^(J2)R^(J3),    -   -L^(J)-NH₂, -L^(J)-NHR^(J1), -L^(J)-NR^(J1) ₂,        -L^(J)-NR^(J2)R^(J3),    -   —O-L^(J)-NH₂, —O-L^(J)-NHR^(J1), —O-L^(J)-NR^(J1) ₂,        —O-L^(J)-NR^(J2)R^(J3),    -   —C(═O)OH, —C(═O)OR^(J1),    -   —C(═O)NH₂, —C(═O)NHR^(J1), —C(═O)NR^(J1) ₂, —C(═O)NR^(J2)R^(J3),    -   —NHC(═O)R^(J1), —NR^(J1)C(═O)R^(J1),    -   —NHC(═O)OR^(J1), —NR^(J1)C(═O)OR^(J1),    -   —OC(═O)NH₂, —OC(═O)NHR^(J1), —OC(═O)NR^(J1) ₂,        —OC(═O)NR^(J2)R^(J3),    -   —C(═O)R^(J1),    -   —NHC(═O)NH₂, —NHC(═O)NHR^(J1),    -   —NHC(═O)NR^(J1) ₂, —NHC(═O)NR^(J2)R^(J3),    -   —NR^(J1)C(═O)NH^(J1) ₂, —NR^(J1)C(═O)NHR^(J1),    -   —NR^(J1)C(═O)NR^(J1) ₂, —NR^(J1)C(═O)NR^(J2)R^(J3),    -   —NHS(═O)₂R^(J1), —NR^(J1)S(═O)₂R^(J1),    -   —S(═O)₂NH₂, —S(═O)₂NHR^(J1), —S(═O)₂NR^(J1) ₂,        —S(═O)₂NR^(J2)R^(J3),    -   —S(═O)R^(J1), —S(═O)₂R^(J1), —OS(═O)₂R^(J1), or —S(═O)₂OR^(J1);

wherein:

-   -   each -L^(J)- is independently saturated aliphatic C₁₋₆alkylene;    -   in each group —NR^(J2)R^(J3), R^(J2) and R^(J3), taken together        with the nitrogen atom to which they are attached, form a 4-,        5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring        heteroatom or exactly 2 ring heteroatoms, wherein one of said        exactly 2 ring heteroatoms is N, and the other of said exactly 2        ring heteroatoms is independently N or O;    -   each —R^(J1) is independently:        -   —R^(K1), —R^(K2), —R^(K3), —R^(K4), —R^(K5), —R^(K6),            —R^(K7), —R^(K8),        -   -L^(K)-R^(K4), -L^(K)-R^(K5), -L^(K)-R^(K6), -L^(K)—R^(K7),            or -L^(K)-R^(K8);    -   wherein:        -   each —R^(K1) is independently saturated aliphatic C₁₋₆alkyl;        -   each —R^(K2) is independently aliphatic C₂₋₆alkenyl;        -   each —R^(K3) is independently aliphatic C₂₋₆alkynyl;        -   each —R^(K4) is independently saturated C₃₋₆cycloalkyl;        -   each —R^(K5) is independently C₃₋₆cycloalkenyl;        -   each —R^(K6) is independently non-aromatic C₃₋₈heterocyclyl;        -   each —R^(K7) is independently C₆₋₁₀carboaryl;        -   each —R^(K8) is independently C₅₋₁₀heteroaryl;        -   each -L^(K)- is independently saturated aliphatic            C₁₋₃alkylene;    -   and wherein:    -   each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkenyl, non-aromatic C₃₋₈heterocyclyl, C₆₋₁₀carboaryl,        C₅₋₁₀heteroaryl, and C₁₋₃alkylene is optionally substituted, for        example, with one or more substituents —R^(K9), wherein each        —R^(K9) is independently:        -   —F, —Cl, —Br, —I,        -   —R^(M1),        -   —CF₃, —OCF₃,        -   —OH, -L^(M)-OH, —O-L^(M)-OH,        -   —OR^(M1), -L^(M)-OR^(M1), —O-L^(M)-OR^(M1),        -   —SH, —SR^(M1),        -   —CN,        -   —NO₂,        -   —NH₂, —NHR^(M1), —NR^(M1) ₂, —NR^(M2)R^(M3),        -   -L^(M)-NH₂, -L^(M)-NHR^(M1), -L^(M)-NR^(M1) ₂,            -L^(M)-NR^(M2)R^(M3),        -   —C(═O)OH, —C(═O)OR^(M1),        -   —C(═O)NH₂, —C(═O)NHR^(M1), —C(═O)NR^(M1) ₂, or            —C(═O)NR^(M2)R^(M3);    -   wherein:    -   each —R^(M1) is independently saturated aliphatic C₁₋₄alkyl,        phenyl, or benzyl;    -   each -L^(M)- is independently saturated aliphatic C₁₋₅alkylene;        and    -   in each group —NR^(M2)R^(M3), R^(M2) and R^(M3), taken together        with the nitrogen atom to which they are attached, form a 4-,        5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring        heteroatom or exactly 2 ring heteroatoms, wherein one of said        exactly 2 ring heteroatoms is N, and the other of said exactly 2        ring heteroatoms is independently N or O.

In one embodiment, each -Q^(A5), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(J1),    -   —CF₃, —OCF₃,    -   —OH, -L^(J)-OH, —O-L^(J)-OH,    -   —OR^(J1), -L^(J)-OR^(J1), —O-L^(J)-OR^(J1),    -   —CN,    -   —NH₂, —NHR^(J1), —NR^(J1) ₂, —NR^(J2)R^(J3),    -   -L^(J)-NH₂, -L^(J)-NHR^(J1), -L^(J)-NR^(J1) ₂,        -L^(J)-NR^(J2)R^(J3),    -   —O-L^(J)-NH₂, —O-L^(J)-NHR^(J1), —O-L^(J)-NR^(J1) ₂,        —O-L^(J)-NR^(J2)R^(J3),    -   —C(═O)OH, —C(═O)OR^(J1),    -   —C(═O)NH₂, —C(═O)NHR^(J1), —C(═O)NR^(J1) ₂, —C(═O)NR^(J2)R^(J3),    -   —NHC(═O)R^(J1), —NR^(J1)C(═O)R^(J1),    -   —NHS(═O)₂R^(J1), —NR^(J1)S(═O)₂R^(J1), or    -   —C(═O)R^(J1).

In one embodiment, each -Q^(A5), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(J1),    -   —NH₂, —NHR^(J1), —NR^(J1) ₂, —NR^(J2)R^(J3),    -   —C(═O)OH, —C(═O)OR^(J1)    -   —C(═O)NH₂, —C(═O)NHR^(J1), —C(═O)NR^(J1) ₂, —C(═O)NR^(J2)R^(J3),    -   —NHC(═O)R^(J1), —NR^(J1)C(═O)R^(J1),    -   —NHS(═O)₂R^(J1), or —NR^(J1)S(═O)₂R^(J1).

In one embodiment, each -Q^(A5), if present, is independently:

-   -   —F, —Cl, —Br, —I, or —R^(J1).

In one embodiment, each -Q^(A5), if present, is independently:

-   -   —NH₂, —NHR^(J1), —NR^(J1) ₂, —NR^(J2)R^(J3),    -   —NHC(═O)R^(J1), —NR^(J1)C(═O)R^(J1),    -   —NHS(═O)₂R^(J1), or —NR^(J1)S(═O)₂R^(J1).

In one embodiment, each -Q^(A5), if present, is independently:

-   -   —NH₂, —NHR^(J1), —NR^(J1) ₂, —NR^(J2)R^(J3),    -   —NHC(═O)R^(J1), or —NR^(J1)C(═O)R^(J1).

In one embodiment, each -Q^(A5), if present, is independently:

-   -   —NHS(═O)₂R^(J1) or —NR^(J1)S(═O)₂R^(J1).

In one embodiment, each -Q^(A5), if present, is independently:

-   -   —C(═O)OH, —C(═O)OR^(J1),    -   —C(═O)NH₂, —C(═O)NHR^(J1), —C(═O)NR^(J1) ₂, or        —C(═O)NR^(J2)R^(J3).

In one embodiment, each -Q^(A5), if present, is independently:

-   -   —C(═O)NH₂, —C(═O)NHR^(J1), —C(═O)NR^(J1) ₂, or        —C(═O)NR^(J2)R^(J3).

In one embodiment, each -Q^(A5), if present, is independently—C(═O)OR^(J1).

In one embodiment, each -Q^(A5), if present, is independently—C(═O)NHR^(J1).

In one embodiment, each -Q^(A5), if present, is independently —R^(J1).

In one embodiment, each -L^(J)-, if present, is independently saturatedaliphatic C₁₋₃alkylene.

In one embodiment, each —NR^(J2)R^(J3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —NR^(J2)R^(J3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —R^(J1), if present, is independently:

-   -   —R^(K1), —R^(K4), —R^(K6), —R^(K7), —R^(K8),    -   -L^(K)-R^(K4), -L^(K)-R^(K6), -L^(K)-R^(K7), or -L^(K)-R^(K8).

In one embodiment, each —R^(J1), if present, is independently:

-   -   —R^(K1), —R^(K6), —R^(K7), —R^(K8),    -   -L^(K)-R^(K6), -L^(K)-R^(K7), or -L^(K)-R¹⁰.

In one embodiment, each —R^(J1), if present, is independently —R^(K1),—R^(K7 , or -L) ^(K)-R^(K7),

In one embodiment, each —R^(J1), if present, is independently —R^(K6),-L^(K)-R^(K8), —R^(K8), or -L^(K)-R^(K8).

In one embodiment, each —R^(J1), if present, is independently —R^(K6),or -L^(K)-R^(K6).

In one embodiment, each —R^(J1), if present, is independently —R^(K1).

In one embodiment, each —R^(J1), if present, is independently —R^(K2).

In one embodiment, each —R^(J1), if present, is independently —R^(K3).

In one embodiment, each —R^(J1), if present, is independently —R^(K7).

In one embodiment, each —R^(J1), if present, is independently —R^(K8).

In one embodiment, each -L^(K)-, if present, is independently —CH₂— or—CH₂CH₂—.

In one embodiment, each -L^(K)-, if present, is independently —CH₂—.

In one embodiment, each —R^(K1), if present, is independently asaturated aliphatic C₁₋₃alkyl.

In one embodiment, each —R^(K1), if present, is independently -Me.

In one embodiment, each —R^(K1), if present, is independently—CH₂CH₂CH₂—OH or —CH₂CH₂CH₂—OMe.

In one embodiment, each —R^(K2), if present, is independently—CH═CH—CH₂—OH, —CH═CH—CH₂—OMe, —CH═CH—CH₂CH₂—OH, or —CH═CH—CH₂CH₂—OMe.

In one embodiment, each —R^(K3), if present, is independently—C≡C—CH₂—OH, —C≡C—CH₂—OMe, —C≡C—C(Me)₂-OH, or —C≡C—C(Me)₂-OMe.

In one embodiment, each —R^(K6), if present, is a C₃₋₈heterocyclylgroupthat is a 4-, 5-, 6-, or 7-membered non-aromatic monocyclic ring or a 7-or 8-membered non-aromatic bicyclic ring, said ring having exactly 1ring heteroatom or exactly 2 ring heteroatoms, wherein each of said ringheteroatoms is independently N, O, or S; and is optionally substituted.

In one embodiment, each —R^(K6), if present, is independentlyazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl,piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl,tetrahydropyranyl, dioxanyl, and is optionally substituted.

In one embodiment, each —R^(K6), if present, is independentlypyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,or tetrahydropyranyl, and is optionally substituted.

In one embodiment, each —R^(K7), if present, is independently phenyl,and is optionally substituted.

In one embodiment, each —R^(K8), if present, is independentlyC₅₋₆heteroaryl, and is optionally substituted.

In one embodiment, each —R^(K8), if present, is independently furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, pyridyl, pyrimidinyl,or pyridazinyl, and is optionally substituted.

In one embodiment, each —R^(K8), if present is independently thiazolyl,oxazolyl, isoxazolyl, or oxadiazolyl, and is optionally substituted.

In one embodiment, each —R^(K8), if present, is independently thienyl orpyrazolyl, and is optionally substituted.

In one embodiment, each —R^(K8), if present, is independently selectedfrom:

In one embodiment, each —R^(K8), if present, is independentlyC₉₋₁₀heteroaryl, and is optionally substituted.

In one embodiment, each —R^(K8), if present, is independentlybenzofuranyl, benzothienyl, indolyl, benzoimidazolyl, indazolyl,benzotriazolyl, benzooxazolyl, benzoisoxazolyl, benzothiazolyl,benzoisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl,phthalazinyl, or quinoxalinyl, and is optionally substituted.

In one embodiment, each —R^(K8), if present is independentlybenzothiazolyl or benzoxazolyl, and is optionally substituted.

In one embodiment, each —R^(K9), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(M1),    -   —CF₃, —OCF₃,    -   —OH, -L^(M)-OH,    -   —OR^(M1), -L^(M)-OR^(M1), —O-L^(M)-OR^(M1),    -   —NH₂, —NHR^(M1), —NR^(M1) ₂, —NR^(M2)R^(M3),    -   -L^(M)-NH₂, -L^(M)-NHR^(M1), -L^(M)-NR^(M1) ₂,        -L^(M)-NR^(M2)R^(M3),    -   —C(═O)OH, —C(═O)OR^(M1),    -   —C(═O)NH₂, —C(═O)NHR^(M1), —C(═O)NR^(M1) ₂, or        —C(═O)NR^(M2)R^(M3).

In one embodiment, each —R^(K9), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(M1),    -   —CF₃, —OCF₃,    -   —OH, -L^(M)-OH,    -   —OR^(M1), -L^(M)-OR^(M1),    -   —NH₂, —NHR^(M1), —NR^(M1) ₂, —NR^(M2)R^(M3),    -   -L^(M)-NH₂, -L^(M)-NHR^(M1), -L^(M)-NR^(M1) ₂,        -L^(M)-NR^(M2)R^(M3),    -   —C(═O)OH, —C(═O)OR^(M1),    -   —C(═O)NH₂, —C(═O)NHR^(M1), —C(═O)NR^(M1) ₂, or        —C(═O)NR^(M2)R^(M3).

In one embodiment, each —R^(K9), if present, is independently:

-   -   —OR^(M1),    -   —NH₂, —NHR^(M1), —NR^(M1) ₂, or —NR^(M2)R^(M3).

In one embodiment, each —R^(K9), if present, is independently:

-   -   —F, —OR^(M1), -L^(M)-OR^(M1), or —O-L^(M)-OR^(M1).

In one embodiment, each —R^(K9), if present, is independently:

-   -   —F, —OMe, —CH₂OMe, or —OCH₂CH₂OMe.

In one embodiment, each -L^(M)-, if present, is independently saturatedaliphatic C₁₋₃alkylene.

In one embodiment, each —R^(M1), if present, is independently C₁₋₄alkyl.

In one embodiment, each —NR^(M2)R^(M3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —NR^(M2)R^(M3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —R^(K9), if present, is independently —F, —Cl,—Br, —I, -Me, -Et, —CF₃, —OH, —CH₂CH₂OH, —OCH₂CH₂OH, —OMe, —OEt,—CH₂CH₂OMe, —OCH₂CH₂OMe, —OCF₃, —SMe, —CN, —NO₂, —NH₂, —NHMe, —NMe₂,—CH₂CH₂NH₂, —CH₂-(morpholino), —O—CH₂CH₂-(morpholino), —O—CH₂CH₂—NH₂,—C(═O)OH, —C(═O)OMe, —C(═O)NH₂, —C(═O)NHMe, —C(═O)NMe₂, —SO₂NH₂,—SO₂NHMe, —SO₂NMe₂, —SO₂Me, —CH₂-Ph, or -Ph.

In one embodiment, each -Q^(A5), if present, is independently selectedfrom those substituents exemplified under the heading “Some PreferredEmbodiments.”

The Group -Q^(A3)

In one embodiment, -Q^(A3), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(N1),    -   —CF₃, —OCF₃,    -   —OH, —OR^(N1),    -   —SH, —SR^(N1),    -   —NH₂, —NHR^(N1), —NR^(N1) ₂, or —NR^(N2)R^(N3);

wherein:

-   -   each —R^(N1) is independently saturated aliphatic C₁₋₆alkyl; and    -   in each group —NR^(N2)R^(N3), R^(N2) and R^(N3), taken together        with the nitrogen atom to which they are attached, form a 4-,        5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring        heteroatom or exactly 2 ring heteroatoms, wherein one of said        exactly 2 ring heteroatoms is N, and the other of said exactly 2        ring heteroatoms is independently N or O.

In one embodiment, each —NR^(N2)R^(N3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —NR^(N2)R^(N3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, -Q^(A3), if present, is independently —F, —Cl, —Br,—I, -Me, -Et, -nPr, -iPr, —CF₃, —OH, —OMe, —OEt, —OCF₃, —SH, —SMe, —NH₂,—NHMe, or —NMe₂.

In one embodiment, -Q^(A3), if present, is independently selected fromthose substituents exemplified under the heading “Some PreferredEmbodiments.”

The Group Q^(B3)

In one embodiment, -Q^(B3), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(Q1),    -   —CF₃, —OCF₃,    -   —OH, —OR^(Q1),    -   —SH, —SR^(Q1),    -   —NH₂, —NHR^(Q1), —NR^(Q1) ₂, or —NR^(Q2)R^(Q3);

wherein:

-   -   each —R^(Q1) is independently saturated aliphatic C₁₋₆alkyl; and    -   in each group —NR^(Q2)R^(Q3), R^(Q2) and R^(Q3), taken together        with the nitrogen atom to which they are attached, form a 4-,        5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring        heteroatom or exactly 2 ring heteroatoms, wherein one of said        exactly 2 ring heteroatoms is N, and the other of said exactly 2        ring heteroatoms is independently N or O.

In one embodiment, -Q^(B3), if present, is independently:

-   -   —R^(Q1),    -   —OH, —OR^(Q1),    -   —SH, —SR^(Q1),    -   —NH₂, —NHR^(Q1), —NR^(Q1) ₂, or —NR^(Q2)R^(Q3).

In one embodiment, each —NR^(Q2)R^(Q3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —NR^(Q2)R^(Q3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, -Q^(B3), if present, is independently -Me, -Et, —OH,—OMe, —OEt, —OCF₃, —NH₂, —NHMe, —NMe₂, —SH, or —SMe.

In one embodiment, -Q^(B3), if present, is independently selected fromthose substituents exemplified under the heading “Some PreferredEmbodiments.”

The Group Q^(B5)

In one embodiment, -Q^(B5), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(T1),    -   —CF₃, —OCF₃,    -   —OH, -L^(T)-OH, —O-L^(T)-OH,    -   —OR^(T1), -L^(T)-OR^(T1), —O-L^(T)-OR^(T1),    -   —SH, —SR^(T1),    -   —CN,    -   —NO₂,    -   —NH₂, —NHR^(T1), —NR^(T1) ₂, —NR^(T2)R^(T3),    -   -L^(T)-NH₂, -L^(T)-NHR^(T1), -L^(T)-NR^(T1) ₂,        -L^(T)-NR^(T2)R^(T3),    -   —O-L^(T)-NH₂, —O-L^(T)-NHR^(T1), —O-L^(T)-NR^(T1) ₂,        —O-L^(T)-NR^(T2)R^(T3),    -   —C(═O)OH, —C(═O)OR^(T1),    -   —C(═O)NH₂, —C(═O)NHR^(T1), —C(═O)NR^(T1) ₂, —C(═O)NR^(T2)R^(T3),    -   —NHC(═O)R^(T1), —NR^(T1)C(═O)R^(T1),    -   —NHC(═O)OR^(T1), —NR^(T1)C(═O)OR^(T1),    -   —OC(═O)NH₂, —OC(═O)NHR^(T1), —OC(═O)NR^(T1) ₂,        —OC(═O)NR^(T2)R^(T3),    -   —C(═O)R^(T1),    -   —NHC(═O)NH₂, —NHC(═O)NHR^(T1),    -   —NHC(═O)NR^(T1) ₂, —NHC(═O)NR^(T2)R^(T3),    -   —NR^(T1)C(═O)NH₂, —NR^(T1)C(═O)NHR^(T1),    -   —NR^(T1)C(═O)NR^(T1) ₂, —NR^(T1)C(═O)NR^(T2)R^(T3),    -   —NHS(═O)₂R^(T1), —NR^(T1)S(═O)₂R^(T1),    -   —S(═O)₂NH₂, —S(═O)₂NHR^(T1), —S(═O)₂NR^(T1) ₂,        —S(═O)₂NR^(T2)R^(T3),    -   —S(═O)R^(T1), —S(═O)₂R^(T1), —OS(═O)₂R^(T1), or —S(═O)₂OR^(T1);

wherein:

-   -   each -L^(T)- is independently saturated aliphatic C₁₋₅alkylene;    -   in each group —NR^(T2)R^(T3), R^(T2) and R^(T3), taken together        with the nitrogen atom to which they are attached, form a 4-,        5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring        heteroatom or exactly 2 ring heteroatoms, wherein one of said        exactly 2 ring heteroatoms is N, and the other of said exactly 2        ring heteroatoms is independently N or O;    -   each —R^(T1) is independently:        -   —R^(U1), —R^(U2), —R^(U3), —R^(U4), —R^(U5), —R^(U6),            —R^(U7), —R^(U8),        -   -L^(U)-R^(U4), -L^(U)-R^(U5), -L^(U)-R^(U6), -L^(U)-R^(U7),            or -L^(U)-R^(U8);    -   wherein:        -   each —R^(U1) is independently saturated aliphatic C₁₋₆alkyl;        -   each —R^(U2) is independently aliphatic C₂₋₆alkenyl;        -   each —R^(U3) is independently aliphatic C₂₋₆alkynyl;        -   each —R^(U4) is independently saturated C₃₋₆cycloalkyl;        -   each —R^(U5) is independently C₃₋₆cycloalkenyl;        -   each —R^(U6) is independently non-aromatic C₃₋₈heterocyclyl;        -   each —R^(U7) is independently C₆₋₁₀carboaryl;        -   each —R^(U8) is independently C₅₋₁₀heteroaryl;        -   each -L^(U)- is independently saturated aliphatic            C₁₋₃alkylene;    -   and wherein:    -   each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkenyl, non-aromatic C₃₋₈heterocyclyl, C₆₋₁₀carboaryl,        C₅₋₁₀heteroaryl, and C₁₋₃alkylene is optionally substituted, for        example, with one or more substituents —R^(U9), wherein each        —R^(U9) is independently:        -   —F, —Cl, —Br, —I,        -   —R^(V1),        -   —CF₃, —OCF₃,        -   —OH, —L^(V)—OH,        -   —OR^(V1), -L^(V)-OR^(V1),        -   —SH, —SR^(V1),        -   —CN,        -   —NO₂,        -   —NH₂, —NHR^(V1), —NR^(V1) ₂, —NR^(V2)R^(V3),        -   -L^(V)-NH₂, -L^(V)-NHR^(V1), -L^(V)-NR^(V1) ₂,            -L^(V)-NR^(V2)R^(V3),        -   —C(═O)OH, —C(═O)OR^(V1),        -   —C(═O)NH₂, —C(═O)NHR^(V1), —C(═O)NR^(V1) ₂, or            —C(═O)NR^(V2)R^(V3);    -   wherein:    -   each —R^(V1) is independently saturated aliphatic C₁₋₄alkyl,        phenyl, or benzyl;    -   each -L^(V)- is independently saturated aliphatic C₁₋₈alkylene;        and    -   in each group —NR^(V2)R^(V3), R^(V2) and R^(V3), taken together        with the nitrogen atom to which they are attached, form a 4-,        5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring        heteroatom or exactly 2 ring heteroatoms, wherein one of said        exactly 2 ring heteroatoms is N, and the other of said exactly 2        ring heteroatoms is independently N or O.

In one embodiment, -Q^(B5), if present, is independently:

-   -   —R^(T1),    -   —CF₃, —OCF₃,    -   —OH, -L^(T)-OH, —O-L^(T)-OH,    -   —OR^(T1), -L^(T)-OR^(T1), —O-L^(T)-OR^(T1),    -   —CN,    -   —NO₂,    -   —NH₂, —NHR^(T1), —NR^(T1) ₂, —NR^(T2)R^(T3)    -   -L^(T)-NH₂, -L^(T)-NHR^(T1), -L^(T)-NR^(T1) ₂,        -L^(T)-NR^(T2)R^(T3)    -   —O-L^(T)-NH₂, —O-L^(T)-NHR^(T1), —O-L^(T)-NR^(T1) ₂,        —O-L^(T)-NR^(T2)R^(T3),    -   —C(═O)OH, —C(═O)OR^(T1),    -   —C(═O)NH₂, —C(═O)NHR^(T1), —C(═O)NR^(T1) ₂, —C(═O)NR^(T2)R^(T3),    -   —NHC(═O)R^(T1), or —NR^(T1)C(═O)R^(T1).

In one embodiment, -Q^(B5), if present, is independently:

-   -   —R^(T1),    -   —CF₃,    -   —OH, -L^(T)-OH,    -   —OR^(T1), -L^(T)-OR^(T1),    -   —CN,    -   —C(═O)NH₂, —C(═O)NHR^(T1), —C(═O)NR^(T1) ₂, —C(═O)NR^(T2)R^(T3),    -   —NHC(═O)R^(T1), or —NR^(T1)C(═O)R^(T1).

In one embodiment, -Q^(B5), if present, is independently:

-   -   —R^(T1),    -   —OR^(T1),    -   —CN,    -   —C(═O)NH₂, —C(═O)NHR^(T1), —C(═O)NR^(T1) ₂, or        —C(═O)NR^(T2)R^(T3).

In one embodiment, each -L^(T)-, if present, is independently saturatedaliphatic C₁₋₃alkylene.

In one embodiment, each —NR^(T2)R^(T3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —NR^(T2)R^(T3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —R^(T1), if present, is independently:

-   -   —R^(U1), —R^(U3), —R^(U4), —R^(U6), —R^(U7), —R^(U8),    -   -L^(U)-R^(U4), -L^(U)-R^(U6), -L^(U)-R^(U7), or -L^(U)-R^(U8).

In one embodiment, each —R^(T1), if present, is independently —R^(U1).

In one embodiment, each -L^(U)-, if present, is independently —CH₂—.

In one embodiment, each —R^(U1), if present, is independently asaturated aliphatic C₁₋₃alkyl.

In one embodiment, each —R^(U1), if present, is independently —CH₃.

In one embodiment, each —R^(U3), if present, is independently analiphatic C₂₋₄alkynyl.

In one embodiment, each —R^(U3), if present, is independently analiphatic C₃alkynyl.

In one embodiment, each —R^(U6), if present, is a C₃₋₈heterocyclylgroupthat is a 4-, 5-, 6-, or 7-membered non-aromatic monocyclic ring or a 7-or 8-membered non-aromatic bicyclic ring, said ring having exactly 1ring heteroatom or exactly 2 ring heteroatoms, wherein each of said ringheteroatoms is independently N, O, or S; and is optionally substituted.

In one embodiment, each —R^(U6), if present, is independentlyazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl,piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl,tetrahydropyranyl, dioxanyl, and is optionally substituted.

In one embodiment, each —R^(U6), if present, is independentlypyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,or tetrahydropyranyl, and is optionally substituted.

In one embodiment, each —R^(U7), if present, is independently phenyl,and is optionally substituted.

In one embodiment, each —R^(U8), if present, is independently C₅₋₆heteroaryl, and is optionally substituted.

In one embodiment, each —R^(U8), if present, is independently furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, orpyridazinyl, and is optionally substituted.

In one embodiment, each —R^(U8), if present, is independentlyimidazolyl, pyrazolyl, or triazolyl, and is optionally substituted.

In one embodiment, each —R^(U9), if present, is independently —F, —Cl,—Br, —I, -Me, -Et, —CF₃, —OH, —CH₂OH, —CH₂CH₂OH, —O—CH₂CH₂OH, —OMe,—OEt, —CH₂OMe, —CH₂CH₂OMe, —O—CH₂CH₂OMe, —OCF₃, —SH, —SMe, —CN, —NO₂,—NH₂, —NHMe, —NMe₂, —CH₂NH₂, —CH₂NHMe, —CH₂NMe₂, —CH₂CH₂NH₂,—CH₂-(morpholino), —O—CH₂CH₂-(morpholino), —O—CH₂CH₂—NH₂, —C(═O)OH,—C(═O)OMe, —C(═O)NH₂, —C(═O)NHMe, —C(═O)NMe₂, —SO₂NH₂, —SO₂NHMe,—SO₂NMe₂, —SO₂Me, —CH₂-Ph, or -Ph.

In one embodiment, each —R^(U9), if present, is independently —F, —Cl,-Me, -Et, —CF₃, —OH, —CH₂OH, —CH₂CH₂OH, —OMe, —CH₂OMe, —CH₂CH₂OMe, —CN,—NO₂, —NH₂, —NHMe, —NMe₂, —CH₂CH₂NH₂, —O—CH₂CH₂—NH₂, —C(═O)OH,—C(═O)OMe, —C(═O)NH₂, —C(═O)NHMe, —C(═O)NMe₂, —SO₂NH₂, —SO₂NHMe, or—SO₂NMe₂.

In one embodiment, -Q^(B5), if present, is independently -Me, —OMe, —CN,—C≡C—CH₂OH, or —C(═O)NH₂.

In one embodiment, -Q^(B5), if present, is independently -Me, —OMe, or—CN.

In one embodiment, -Q^(B5), if present, is independently -Me or —CN.

In one embodiment, -Q^(B5), if present, is independently —CN.

In one embodiment, -Q^(B5), if present, is independently selected fromthose substituents exemplified under the heading “Some PreferredEmbodiments.”

The Group Q^(B6)

In one embodiment, -Q^(B6), if present, is independently:

-   -   —R^(W1),    -   —CF₃, —OCF₃,    -   —OH, -L^(W)-OH, —O-L^(W)-OH,    -   —OR^(W1), -L^(W)-OR^(W1), —O-L^(W)-OR^(W1),    -   —SH, —SR^(W1),    -   —CN,    -   —NO₂,    -   —NH₂, —NHR^(W1), —NR^(W1) ₂, —NR^(W2)R^(W3),    -   -L^(W)-NH₂, -L^(W)-NHR^(W1), -L^(W)-NR^(W1) ₂,        -L^(W)-NR^(W2)R^(W3),    -   —O-L^(W)-NH₂, —O-L^(W)-NHR^(W1), —O-L^(W)-NR^(W1) ₂,        —O-L^(W)-NR^(W2)R^(W3),    -   —C(═O)OH, —C(═O)OR^(W1),    -   —C(═O)NH₂, —C(═O)NHR^(W1), —C(═O)NR^(W1) ₂, —C(═O)NR^(W2)R^(W3),    -   —NHC(═O)R^(W1), —NR^(W1)C(═O)R^(W1),    -   —NHC(═O)OR^(W1), —NR^(W1)C(═O)OR^(W1),    -   —OC(═O)NH₂, —OC(═O)NHR^(W1), —OC(═O)NR^(W1) ₂,        —OC(═O)NR^(W2)R^(W3)    -   —C(═O)R^(W1),    -   —NHC(═O)NH₂, —NHC(═O)NHR^(W1),    -   —NHC(═O)NR^(W1) ₂, —NHC(═O)NR^(W2)R^(W3),    -   —NR^(W1)C(═O)NH₂, —NR^(W1)C(═O)NHR^(W1),    -   —NR^(W1)C(═O)NRW^(W1) ₂, —NR^(W1)C(═O)NR^(W2)R^(W3),    -   —NHS(═O)₂R^(W1), —NR^(W1)S(═O)₂R^(W1),    -   —S(═O)₂NH₂, —S(═O)₂NHR^(W1), —S(═O)₂NR^(W1) ₂,        —S(═O)₂NR^(W2)R^(W3),    -   —S(═O)R^(W1), —S(═O)₂R^(W1), —OS(═O)₂R^(W1), or —S(═O)₂OR^(W1);

wherein:

-   -   each -L^(W)- is independently saturated aliphatic C₁₋₅alkylene;    -   in each group —NR^(W2)R^(W3), R^(W2) and R^(W3), taken together        with the nitrogen atom to which they are attached, form a 4-,        5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring        heteroatom or exactly 2 ring heteroatoms, wherein one of said        exactly 2 ring heteroatoms is N, and the other of said exactly 2        ring heteroatoms is independently N or O;    -   each —R^(W1) is independently:        -   —R^(X1), —R^(X2), —R^(X3), —R^(X4), —R^(X5), —R^(X6),            —R^(X7), —R^(X8),        -   -L^(X)—R^(X4), -L^(X)-R^(X5), -L^(X)-R^(X6), -L^(X)-R^(X7),            or -L^(X)-R^(X8);    -   wherein:        -   each —R^(X1) is independently saturated aliphatic C₁₋₆alkyl;        -   each —R^(X2) is independently aliphatic C₂₋₆alkenyl;        -   each —R^(X3) is independently aliphatic C₂₋₆alkynyl;        -   each —R^(X4) is independently saturated C₃₋₆cycloalkyl;        -   each —R^(X5) is independently C₃₋₆cycloalkenyl;        -   each —R^(X6) is independently non-aromatic C₃₋₈heterocyclyl;        -   each —R^(X7) is independently C₆₋₁₀carboaryl;        -   each —R^(X8) is independently C₆₋₁₀heteroaryl;        -   each -L^(X)- is independently saturated aliphatic            C₁₋₃alkylene;    -   and wherein:    -   each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkenyl, non-aromatic C₃₋₈heterocyclyl, C₆₋₁₀carboaryl,        C₅₋₁₀heteroaryl, and C₁₋₃alkylene is optionally substituted, for        example, with one or more substituents —R^(X9), wherein each        —R^(X9) is independently:        -   —F, —Cl, —Br, —I,        -   —R^(Y1),        -   —CF₃, —OCF₃,        -   —OH, -L^(Y)-OH,        -   —OR^(Y1), -L^(Y)-OR^(Y1),        -   —SH, —SR^(Y1),        -   —CN,        -   —NO₂,        -   —NH₂, —NHR^(Y1), —NR^(Y1) ₂, —NR^(Y2)R^(Y3),        -   -L^(Y)-NH₂, -L^(Y)-NHR^(Y1), -L^(Y)-NR^(Y1)            ₂,-L^(Y)-NR^(Y2)R^(Y3),        -   —C(═O)OH, —C(═O)OR^(Y1),        -   —C(═O)NH₂, —C(═O)NHR^(Y1), —C(═O)NR^(Y1) ₂, or            —C(═O)NR^(Y2)R^(Y3);    -   wherein:    -   each —R^(Y1) is independently saturated aliphatic C₁₋₄alkyl,        phenyl, or benzyl;    -   each -L^(Y)- is independently saturated aliphatic C₁₋₅alkylene;        and    -   in each group —NR^(Y2)R^(Y3), R^(Y2) and R^(Y3), taken together        with the nitrogen atom to which they are attached, form a 4-,        5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring        heteroatom or exactly 2 ring heteroatoms, wherein one of said        exactly 2 ring heteroatoms is N, and the other of said exactly 2        ring heteroatoms is independently N or O.

In one embodiment, -Q^(B6), if present, is independently:

-   -   —R^(W1),    -   —CF₃, —OCF₃,    -   —OH, -L^(W)-OH, —O-L^(W)-OH,    -   —OR^(W1), -L^(W)-OR^(W1), —O-L^(W)-OR^(W1),    -   —CN,    -   —NH₂, —NHR^(W1), —NR^(W1) ₂, —NR^(W2)R^(W3),    -   -L^(W)-NH₂, -L^(W)-NHR^(W1), -L^(W)-NR^(W1) ₂,        -L^(W)-NR^(W2)R^(W3),    -   —O-L^(W)-NH₂, —O-L^(W)-NHR^(W1), —O-L^(W)-NR^(W1) ₂,        —O-L^(W)-NR^(W2)R^(W3),    -   —C(═O)OH, —C(═O)OR^(W1),    -   —C(═O)NH₂, —C(═O)NHR^(W1), —C(═O)NR^(W1) ₂, —C(═O)NR^(W2)R^(W3),    -   —NHC(═O)R^(W1), —NR^(W1)C(═O)R^(W1),    -   —NHC(═O)OR^(W1), —NR^(W1)C(═O)OR^(W1),    -   —OC(═O)NH₂, —OC(═O)NHR^(W1), —OC(═O)NR^(W1) ₂,        —OC(═O)NR^(W2)R^(W3),    -   —NHC(═O)NH₂, —NHC(═O)NHR^(W1),    -   —NHC(═O)NR^(W1) ₂, —NHC(═O)NR^(W2)R^(W3),    -   —NR^(W1)C(═O)NH₂, —NR^(W1)C(═O)NHR^(W1),    -   —NR^(W1)C(═O)NR^(W1) ₂, —NR^(W1)C(═O)NR^(W2)R^(W3),    -   —NHS(═O)₂R^(W1), or —NR^(W1)S(═O)₂R^(W1),

In one embodiment, -Q^(B6), if present, is independently:

-   -   —R^(W1),    -   —CF₃, —OCF₃,    -   —OH, -L^(W)-OH, —O-L^(W)-OH,    -   —OR^(W1), -L^(W)-OR^(W1), —O-L^(W)-OR^(W1),    -   —CN,    -   —NH₂, —NHR^(W1), —NR^(W1) ₂, —NR^(W2)R^(W3),    -   -L^(W)-NH₂, -L^(W)-NHR^(W1), -L^(W)-NR^(W1) ₂,        -L^(W)-NR^(W2)R^(W3),    -   —O-L^(W)-NH₂, —O-L^(W)-NHR^(W1), —O-L^(W)-NR^(W1) ₂, or        —O-L^(W)-NR^(W2)R^(W3).

In one embodiment, each -L^(W)-, if present, is independently saturatedaliphatic C₁₋₃alkylene.

In one embodiment, each —NR^(W2)R^(W3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —NR^(W2)R^(W3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —R^(W1), if present, is independently:

-   -   —R^(X1), —R^(X4), —R^(X6), —R^(X7), —R^(X8),    -   -L^(X)-R^(X4), -L^(X)-R^(X6), -L^(X)-R^(X7), or -L^(X)-R^(X8).

In one embodiment, each —R^(W1), if present, is independently —R^(X1).

In one embodiment, each -L^(X)-, if present, is independently —CH₂—.

In one embodiment, each —R^(X1), if present, is independently asaturated aliphatic C₁₋₃alkyl.

In one embodiment, each —R^(X6), if present, is a C₃₋₈heterocyclyl groupthat is a 4-, 5-, 6-, or 7-membered non-aromatic monocyclic ring or a 7-or 8-membered non-aromatic bicyclic ring, said ring having exactly 1ring heteroatom or exactly 2 ring heteroatoms, wherein each of said ringheteroatoms is independently N, O, or S; and is optionally substituted.

In one embodiment, each —R^(X6), if present, is independentlyazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl,piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl,tetrahydropyranyl, dioxanyl, 8-aza-bicyclo[3.2.1]octanyl,3,8-diaza-bicyclo[3.2.1]octanyl, 6-aza-bicyclo[3.1.1]heptanyl, or3,6-diaza-bicyclo[3.1.1]heptanyl, and is optionally substituted.

In one embodiment, each —R^(X6), if present, is independentlypyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,or tetrahydropyranyl, and is optionally substituted.

In one embodiment, each —R^(X7), if present, is independently phenyl,and is optionally substituted.

In one embodiment, each —R^(X8), if present, is independentlyC₅₋₆heteroaryl, and is optionally substituted.

In one embodiment, each —R^(X8), if present, is independently furanyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, orpyridazinyl, and is optionally substituted.

In one embodiment, each —R^(X9), if present, is independently:

-   -   —F, —Cl, —Br, —I,    -   —R^(Y1),    -   —CF₃, —OCF₃,    -   —OH, -L^(Y)-OH,    -   —OR^(Y1), -L^(Y)-OR^(Y1),    -   —NH₂, —NHR^(Y1), —NR^(Y1) ₂, —NR^(Y2)R^(Y3),    -   -L^(Y)-NH₂, -L^(Y)-NHR^(Y1), -L^(Y)-NR^(Y1) ₂,        -L^(Y)-NR^(Y2)R^(Y3),    -   —C(═O)OH, —C(═O)OR^(Y1),    -   —C(═O)NH₂, —C(═O)NHR^(Y1), —C(═O)NR^(Y1) ₂, or        —C(═O)NR^(Y2)R^(Y3).

In one embodiment, each -L^(Y)-, if present, is independently saturatedaliphatic C₁₋₃alkylene.

In one embodiment, each —R^(Y1), if present, is independently C₁₋₄alkyl.

In one embodiment, each —NR^(Y2)R^(Y3), if present, is independentlyazetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino,piperazino, morpholino, azepino, or diazepino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —NR^(Y2)R^(Y3), if present, is independentlypyrrolidino, piperidino, piperazino, or morpholino, and is optionallysubstituted, for example, with one or more groups selected fromC₁₋₃alkyl and —CF₃.

In one embodiment, each —R^(X6), if present, is independently —F, —Cl,—Br, —I, -Me, -Et, —CF₃, —OH, —CH₂OH, —CH₂CH₂OH, —O—CH₂CH₂OH, —OMe,—OEt, —CH₂OMe, —CH₂CH₂OMe, —O—CH₂CH₂OMe, —OCF₃, —SMe, —CN, —NO₂, —NH₂,—NHMe, —NMe₂, —CH₂NH₂, —CH₂NHMe, —CH₂NMe₂, —CH₂CH₂NH₂,—CH₂-(morpholino), —O—CH₂CH₂-(morpholino), —O—CH₂CH₂—NH₂, —C(═O)OH,—C(═O)OMe, —C(═O)NH₂, —C(═O)NHMe, —C(═O)NMe₂, —SO₂NH₂, —SO₂NHMe,—SO₂NMe₂, —SO₂Me, —CH₂-Ph, or -Ph.

In one embodiment, -Q^(B6), if present, is independently -Me, -Et, -nPr,-iPr, —CF₃, —OH, —OMe, —OEt, —O(nPr), —O(iPr), —OCF₃, —CN, —NH₂, —NHMe,—NMe₂, —O—CH₂CH₂—OH, —O—CH₂CH₂—OMe, —O—CH₂CH₂—NH₂, —O—CH₂CH₂—NHMe,—O—CH₂CH₂—NMe₂, —O—CH₂CH₂CH₂—NH₂, —O—CH₂CH₂CH₂—NHMe, or—O—CH₂CH₂CH₂—NMe₂.

In one embodiment, -Q^(B6), if present, is independently selected fromthose substituents exemplified under the heading “Some PreferredEmbodiments.”

Molecular Weight

In one embodiment, the BA compound has a molecular weight of from 187 to1200.

In one embodiment, the bottom of range is 190, 200, 225, 250, 275, 300,or 350.

In one embodiment, the top of range is 1100, 1000, 900, 800, 700, or600.

In one embodiment, the range is from 190 to 600.

Combinations

Each and every compatible combination of the embodiments described aboveis explicitly disclosed herein, as if each and every combination wasindividually and explicitly recited.

Examples of Specific Embodiments

In one embodiment, the compounds are selected from compounds of thefollowing formulae and pharmaceutically acceptable salts, solvates,chemically protected forms, and prodrugs thereof:

Compound Synthesis No. No. Structure Y-001 44-D

Y-002 45

Y-003 46

Y-004 47

Y-005 48

Y-006 49

Y-007 50

Y-008 51

Y-009 52

Y-010 53

Y-011 54

Y-012 55

Y-013 56

Y-014 57

Y-015 58

Y-016 59

Y-017 60

Y-018 61

Y-019 62-C

Y-020 63

Y-021 64

Y-022 65

Y-023 66

Y-024 67

Y-025 68

Y-026 69

Y-027 70

Y-028 71

Y-029 72

Y-030 73

Y-031 74

Y-032 75-B

Y-033 76

Y-034 77

Y-035 78-C

Y-036 81

Y-037 82-B

Y-038 83-D

Y-039 84-B

In one embodiment, the compounds are selected from compounds of thefollowing formulae and pharmaceutically acceptable salts, solvates,chemically protected forms, and prodrugs thereof:

Compound Synthesis No No Structure Y-040  85

Y-041  86

Y-042  87

Y-043  88

Y-044  89

Y-045  90

Y-046  91

Y-047  92

Y-048  93

Y-049  94

Y-050  95

Y-051  96

Y-052  97

Y-053  98

Y-054  99

Y-055 100

Y-056 101-D

Y-057 102

Y-058 103

Y-059 104

Y-060 105

Y-061 106

Y-062 107-C

Y-063 108

Y-064 109-D

Y-065 110-B

Y-066 111-B

Y-067 112

Y-068 113

Y-069 114

Y-070 115

Y-071 116

Y-072 117-B

Y-073 118

Y-074 119

Y-075 120

Y-076 121

Y-077 122

Y-078 123

Y-079 124

Y-080 125

Y-081 126

Y-082 127

Y-083 128

Y-084 129

Y-085 130

Y-086 131

Y-087 132

Y-088 133

Y-089 134

Y-090 135

Y-091 136

Y-092 137

Y-093 138

Y-094 139

Y-095 140

Y-096 141

Y-097 142

Y-098 143

Y-099 144

Y-100 145

Y-101 146

Y-102 147

Y-103 148

Y-104 149

Y-105 150

Y-106 151

Y-107 152-C

Y-108 153-E

Y-109 154

Y-110 155-D

Y-111 156-B

Y-112 157

Y-113 158

Y-114 159

Y-115 160

Y-116 161

Y-117 162

Y-118 163

Y-119 164

Y-120 165

Y-121 166

Y-122 167-E

Y-123 168-B

Y-124 169-D

Y-125 170-E

Y-126 171-E

Y-127 172

Y-128 173

Y-129 174

Y-130 175

Y-131 176

Y-132 177

Y-133 178

Y-134 179

Y-135 180

Y-136 181

Y-137 182

Y-138 183

Y-139 184-C

Y-140 185

Y-141 186

Y-142 187

Y-143 188

Y-144 189-B

Y-145 190

Y-146 191-H

Y-147 192-H

Y-148 193

Y-149 194

Y-150 195

Y-151 196

Y-152 197

Y-153 198

Y-154 199

Y-155 200

Y-156 201

Y-157 202

Y-158 203

Y-159 204

In one embodiment, the compounds are selected from compounds of thefollowing formulae and pharmaceutically acceptable salts, solvates,chemically protected forms, and prodrugs thereof:

Compound Synthesis No. No. Structure Z-001  1-B

Z-002  2

Z-003  3

Z-004  4

Z-005  5

Z-006  6

Z-007  7-B

Z-008  8

Z-009  9

Z-010 10

Z-011 11

Z-012 12

Z-013 13

Z-014 14

Z-015 15

Z-016 16

Z-017 17

Z-018 18

Z-019 19

Z-020 20

Z-021 21

Z-022 22

Z-023 23

Z-024 24

Z-025 25

Z-026 26

Z-027 27

Z-028 28

Z-029 29

Z-030 30

Z-031 31

Z-032 32

Z-033 33

Z-034 34

Z-035 35

Z-036 36

Z-037 37

Z-038 38

Z-039 39

Z-040 40

Z-041 41

Z-042 42

Z-043 43

Z-044 79-E

Z-045 80

In one embodiment, the compounds are selected from compounds of thefollowing formula and pharmaceutically acceptable salts, solvates,chemically protected forms, and prodrugs thereof:

Compound Synthesis No No. Structure Z-046 205-D

Substantially Purified Forms

One aspect of the present invention pertains to BAA compounds, asdescribed herein, in substantially purified form and/or in a formsubstantially free from contaminants.

In one embodiment, the substantially purified form is at least 50% byweight, e.g., at least 60% by weight, e.g., at least 70% by weight,e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., atleast 95% by weight, e.g., at least 97% by weight, e.g., at least 98% byweight, e.g., at least 99% by weight.

Unless specified, the substantially purified form refers to the compoundin any stereoisomeric or enantiomeric form. For example, in oneembodiment, the substantially purified form refers to a mixture ofstereoisomers, i.e., purified with respect to other compounds. In oneembodiment, the substantially purified form refers to one stereoisomer,e.g., optically pure stereoisomer. In one embodiment, the substantiallypurified form refers to a mixture of enantiomers. In one embodiment, thesubstantially purified form refers to a equimolar mixture of enantiomers(i.e., a racemic mixture, a racemate). In one embodiment, thesubstantially purified form refers to one enantiomer, e.g., opticallypure enantiomer.

In one embodiment, the contaminants represent no more than 50% byweight, e.g., no more than 40% by weight, e.g., no more than 30% byweight, e.g., no more than 20% by weight, e.g., no more than 10% byweight, e.g., no more than 5% by weight, e.g., no more than 3% byweight, e.g., no more than 2% by weight, e.g., no more than 1% byweight.

Unless specified, the contaminants refer to other compounds, that is,other than stereoisomers or enantiomers. In one embodiment, thecontaminants refer to other compounds and other stereoisomers. In oneembodiment, the contaminants refer to other compounds and the otherenantiomer.

In one embodiment, the substantially purified form is at least 60%optically pure (i.e., 60% of the compound, on a molar basis, is thedesired stereoisomer or enantiomer, and 40% is the undesiredstereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., atleast 80% optically pure, e.g., at least 90% optically pure, e.g., atleast 95% optically pure, e.g., at least 97% optically pure, e.g., atleast 98% optically pure, e.g., at least 99% optically pure.

Isomers

Certain compounds may exist in one or more particular geometric,optical, enantiomeric, diasteriomeric, epimeric, atropic,stereoisomeric, tautomeric, conformational, or anomeric forms, includingbut not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, andr-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d-and I-forms; (+) and (−) forms; keto-, enol-, and enolate-forms; syn-and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axialand equatorial forms; boat-, chair-, twist-, envelope-, andhalfchair-forms; and combinations thereof, hereinafter collectivelyreferred to as “isomers” (or “isomeric forms”).

Note that, except as discussed below for tautomeric forms, specificallyexcluded from the term “isomers,” as used herein, are structural (orconstitutional) isomers (i.e., isomers which differ in the connectionsbetween atoms rather than merely by the position of atoms in space). Forexample, a reference to a methoxy group, —OCH₃, is not to be construedas a reference to its structural isomer, a hydroxymethyl group, —CH₂OH.Similarly, a reference to ortho-chlorophenyl is not to be construed as areference to its structural isomer, meta-chlorophenyl. However, areference to a class of structures may well include structurallyisomeric forms falling within that class (e.g., C₁-,alkyl includesn-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl;methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example,keto-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto/enol (illustrated below), imine/enamine,amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.

Note that specifically included in the term “isomer” are compounds withone or more isotopic substitutions. For example, H may be in anyisotopic form, including ¹H, ²H (D), and ³H (T); C may be in anyisotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopicform, including ¹⁶O and ¹⁸O; and the like.

Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including mixtures (e.g., racemicmixtures) thereof. Methods for the preparation (e.g., asymmetricsynthesis) and separation (e.g., fractional crystallisation andchromatographic means) of such isomeric forms are either known in theart or are readily obtained by adapting the methods taught herein, orknown methods, in a known manner.

Salts

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g., —COOH may be —COO⁻), then a salt may be formedwith a suitable cation. Examples of suitable inorganic cations include,but are not limited to, alkali metal ions such as Na⁺ and K⁺, alkalineearth cations such as Ca²⁺ and Mg²⁺, and other cations such as Al⁺³.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammoniumions are those derived from: ethylamine, diethylamine,dicyclohexylamine, triethylamine, butylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, benzylamine,phenylbenzylamine, choline, meglumine, and tromethamine, as well asamino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group which may becationic (e.g., —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to,those derived from the following organic acids: 2-acetyoxybenzoic,acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric,edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic,gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic,methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic,succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examplesof suitable polymeric organic anions include, but are not limited to,those derived from the following polymeric acids: tannic acid,carboxymethyl cellulose.

Unless otherwise specified, a reference to a particular compound alsoincludes salt forms thereof.

Solvates and Hydrates

It may be convenient or desirable to prepare, purify, and/or handle acorresponding solvate of the compound. The term “solvate” is used hereinin the conventional sense to refer to a complex of solute (e.g.,compound, salt of compound) and solvent. If the solvent is water, thesolvate may be conveniently referred to as a hydrate, for example, amono-hydrate, a di-hydrate, a tri-hydrate, etc.

Unless otherwise specified, a reference to a particular compound alsoincludes solvate and hydrate forms thereof.

Chemically Protected Forms

It may be convenient or desirable to prepare, purify, and/or handle thecompound in a chemically protected form. The term “chemically protectedform” is used herein in the conventional chemical sense and pertains toa compound in which one or more reactive functional groups are protectedfrom undesirable chemical reactions under specified conditions (e.g.,pH, temperature, radiation, solvent, and the like). In practice, wellknown chemical methods are employed to reversibly render unreactive afunctional group, which otherwise would be reactive, under specifiedconditions. In a chemically protected form, one or more reactivefunctional groups are in the form of a protected or protecting group(also known as a masked or masking group or a blocked or blockinggroup). By protecting a reactive functional group, reactions involvingother unprotected reactive functional groups can be performed, withoutaffecting the protected group; the protecting group may be removed,usually in a subsequent step, without substantially affecting theremainder of the molecule. See, for example, Protective Groups inOrganic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley andSons, 2006).

Unless otherwise specified, a reference to a particular compound alsoincludes chemically protected forms thereof.

A wide variety of such “protecting,” “blocking,” or “masking” methodsare widely used and well known in organic synthesis. For example, acompound which has two nonequivalent reactive functional groups, both ofwhich would be reactive under specified conditions, may be derivatizedto render one of the functional groups “protected,” and thereforeunreactive, under the specified conditions; so protected, the compoundmay be used as a reactant which has effectively only one reactivefunctional group. After the desired reaction (involving the otherfunctional group) is complete, the protected group may be “deprotected”to return it to its original functionality.

For example, a hydroxy group may be protected as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl,benzhydryl(diphenylmethyl), or trityl(triphenylmethyl)ether; atrimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester(—OC(═O)CH₃, —OAc).

For example, an aldehyde or ketone group may be protected as an acetal(R—CH(OR)₂) or ketal (R₂C(OR)₂), respectively, in which the carbonylgroup (>C═O) is converted to a diether (>C(OR)₂), by reaction with, forexample, a primary alcohol. The aldehyde or ketone group is readilyregenerated by hydrolysis using a large excess of water in the presenceof acid.

For example, an amine group may be protected, for example, as an amide(—NRCO—R) or a urethane (—NRCO—OR), for example, as: a methyl amide(—NHCO—CH₃); a benzyloxy amide (—NHCO—OCH₂C₆H₅, —NH-Cbz); as a t-butoxyamide (—NHCO—OC(CH₃)₃, —NH-Boc); a 2-biphenyl-2-propoxy amide(—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH-Bpoc), as a 9-fluorenylmethoxy amide(—NH-Fmoc), as a 6-nitroveratryloxy amide (—NH-Nvoc), as a2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxyamide (—NH-Troc), as an allyloxy amide (—NH-Alloc), as a2(-phenylsulfonyl)ethyloxy amide (—NH-Psec); or, in suitable cases(e.g., cyclic amines), as a nitroxide radical (>N—O.).

For example, a carboxylic acid group may be protected as an ester forexample, as: an C₁₋₇alkyl ester (e.g., a methyl ester; a t-butyl ester);a C₁₋₇haloalkyl ester (e.g., a C₁₋₇trihaloalkyl ester); atriC₁₋₇alkylsilyl-C₁₋₇alkyl ester; or a C₅₋₂₀aryl-C₁₋₇alkyl ester (e.g.,a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as amethyl amide.

For example, a thiol group may be protected as a thioether (—SR), forexample, as: a benzyl thioether; an acetamidomethyl ether(—S—CH₂NHC(═O)CH₃).

Prodrugs

It may be convenient or desirable to prepare, purify, and/or handle thecompound in the form of a prodrug. The term “prodrug,” as used herein,pertains to a compound which, when metabolised (e.g., in vivo), yieldsthe desired active compound. Typically, the prodrug is inactive, or lessactive than the desired active compound, but may provide advantageoushandling, administration, or metabolic properties.

Unless otherwise specified, a reference to a particular compound alsoincludes prodrugs thereof.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyof the carboxylic acid groups (—C(═O)OH) in the parent compound, with,where appropriate, prior protection of any other reactive groups presentin the parent compound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). Forexample, the prodrug may be a sugar derivative or other glycosideconjugate, or may be an amino acid ester derivative.

Chemical Synthesis

Several methods for the chemical synthesis of biarylamine compounds ofthe present invention are described herein. These and/or other wellknown methods may be modified and/or adapted in known ways in order tofacilitate the synthesis of additional compounds within the scope of thepresent invention.

In one approach (General Method A), compounds of type (iv) are preparedby a method as illustrated in the following scheme. Commerciallyavailable compounds (i) and (ii) are coupled, for example, underpalladium mediated amination conditions, typically with heating and inthe presence of base, to give diarylamine (iii). Subsequent reactionwith an amine, usually in the presence of a tertiary base such astriethylamine at elevated temperatures in NMP using oil bath ormicrowave heating, followed by removal of any protecting groups on theamine component, gives the required compound (iv). Alternatively, theorder of sequential displacement by the two amines can be reversed.

In another approach (General Method B), compounds of type (vii) areprepared by a method as illustrated in the following scheme.Commercially available compounds (i) and (v) are coupled, for example,under palladium mediated amination conditions, typically with heatingand in the presence of base to give diarylamine (vi). Subsequentreaction with an amine, usually in the presence of a tertiary base suchas triethylamine at elevated temperatures in NMP using oil bath ormicrowave heating, followed by removal of any protecting groups on theamine component, gives the required compound (vii). Alternatively, theorder of sequential displacement by the two amines can be reversed.

In another approach (General Method C), compounds of type (xi) areprepared by a method as illustrated in the following scheme.2-Bromo-4-chloro-5-nitropyridine (viii) is treated with an amine,typically in acetonitrile and in the presence of a tertiary base toafford intermediate (ix). Treatment of this intermediate with2-amino-5-cyanopyrazine (v) under palladium mediated aminationconditions, typically with heating and in the presence of base, givesbisarylamine (x). Reduction of the nitro group using tin(II)chloride ora metal/acid mixture followed by removal of any protecting groups on theamine component gives compound (xi).

In another approach (General Method D), compounds of type (xii) and(xiii) are prepared by a method as illustrated in the following scheme.Amine (xi) is treated with an acid under standard amide formationconditions using an activating agent such as EDC. Alternatively, theamine is treated with an anhydride or other form of activated acid.Removal of any protecting groups on the amine component then givesamides (xii). Treatment of amine (xi) with a sulphonyl chloridetypically in the presence of a tertiary base such as triethylamine givesrise to sulphonamides (xiii).

In another approach (General Method E), compounds of type (xvi) areprepared by a method as illustrated in the following scheme.2-Bromo-4-chloro-5-nitropyridine (viii) is treated with an alcohol andstrong base such as sodium hydride, typically in DMF to affordintermediate (xiv). Treatment of this intermediate with2-amino-5-cyanopyrazine (v) under palladium mediated aminationconditions, typically with heating and in the presence of base, givesdiarylamine (xv). Reduction of the nitro group using tin(II)chloride ora metal/acid mixture followed by removal of any protecting groups on thealcohol component then provides compound (xvi).

In another approach (General Method F), compounds of type (xvii) areprepared by a method as illustrated in the following scheme. Amine (xvi)is treated with an acid under standard amide formation conditions usingan activating agent such as EDC. Alternatively, the amine is treatedwith an anhydride or other form of activated acid. Removal of anyprotecting groups on the amine component then gives amides (xvii).

In another approach (General Method G), compounds of type (xxi) areprepared by a method as illustrated in the following scheme. Treatmentof dichloropyrimidine (i) with an amine, typically with heating and inthe presence of a tertiary base, provides intermediate (xviii).Sonagashira coupling of 2-bromo-5-aminopyrazine (xix) and an alkynegives amine (xx). Treatment of intermediate (xviii) with (xx) underpalladium mediated amination conditions, typically with heating and inthe presence of base gives, after removal of any protecting groups,biarylamines (xxi).

In another approach (General Method H), compounds of type (xxii) areprepared by a method as illustrated in the following scheme. Nitriles(vii) are treated with trifluoroacetic acid, typically with heating, toprovide primary amides (xxii).

In another approach (General Method I), compounds of type (xxv) areprepared by a method as illustrated in the following scheme.2,4-Dichloropyridine-5-carboxylates (xxiii) are treated with amines,typically with oil bath or microwave heating, and typically in thepresence of a tertiary amine base, to provide pyridines (xxiv).Treatment of intermediates (xxiv) with (v) under palladium mediatedamination conditions, typically with heating and in the presence of basegives, after removal of any protecting groups, biarylamines (xxv).

In another approach (General Method J), compounds of type (xxviii) areprepared by a method as illustrated in the following scheme. Esters(xxvi) are hydrolysed to the acids (xxvii) with alkoxides, typicallylithium hydroxide. The acids (xxvii) are treated with an amine understandard amide formation conditions using an activating agent such asTBTU.

In another approach (General Method K), compounds of type (xxxii) areprepared by a method as illustrated in the following scheme.2-Amino-4,5-dichloropyridine (xxix) is treated with an amine, typicallywith oil bath or microwave heating, to give the 5-chloropyridine (xxx).Treatment of intermediate (xxx) with (v) under palladium mediatedamination conditions, typically with heating and in the presence of basegives intermediate (xxxi). Treatment of the intermediate (xxxi) with anarylboronic acid or arylboronic ester under palladium mediatedcross-coupling conditions, typically with heating and in the presence ofbase gives, after removal of any protecting groups, biarylamines(xxxii).

In another approach (General Method L), compounds of type (xxxiv) areprepared by a method as illustrated in the following scheme.2,4-Dichloropyridine-5-carboxylates (xxiii) are treated with amines,typically with oil bath or microwave heating, and typically in thepresence of a tertiary amine base, to provide pyridines (xxiv).Treatment of intermediates (xxiv) with commercially available2-amino-5-methylpyrazine (xxxiii) under palladium mediated aminationconditions, typically with heating and in the presence of base gives,after removal of any protecting groups, biarylamines (xxxiv).

In another approach, (General Method M), compounds of type (xxxvi) areprepared by a method as illustrated in the following scheme.2,4-Dichloropyridine-5-carboxylates (xxiii) are treated with amines,typically with oil bath or microwave heating, and typically in thepresence of a tertiary amine base, to provide pyridines (xxiv).Treatment of intermediates (xxiv) with 2-amino-5-methoxypyrazine (xxxv)under palladium mediated amination conditions, typically with heatingand in the presence of base gives, after removal of any protectinggroups, biarylamines (xxxvi).

In another approach (General Method N), compounds of type (xxxxii) areprepared by a method illustrated in the following scheme.2-Chloro-4-amino-5-iodopyridine (xxxvii) is alkylated with alkyl halidesor alkyl tosylates (xxxviii) in the presence of a strong base, forexample sodium hydride, typically with heating. The intermediates(xxxix) are treated with an aryl or alkenyl boronic acid (xxxx) in thepresence of a palladium catalyst and base, typicallypalladium(0)tetrakis(triphenylphosphine) and sodium carbonate, in asuitable solvent such as acetonitrile, with oil bath or microwaveheating, to give the intermediates (xxxxi). The intermediates (xxxxi)are reacted with 2-amino-4-cyanopyrazine (v) under palladium mediatedamination conditions, typically with heating and in the presence ofbase, to give, after removal of any protecting groups, biarylamines(xxxxii).

Compositions

One aspect of the present invention pertains to a composition (e.g., apharmaceutical composition) comprising a BAA compound, as describedherein, and a pharmaceutically acceptable carrier, diluent, orexcipient.

Another aspect of the present invention pertains to a method ofpreparing a composition (e.g., a pharmaceutical composition) comprisingadmixing a BAA compound, as described herein, and a pharmaceuticallyacceptable carrier, diluent, or excipient.

Uses

The compounds described herein are useful, for example, in the treatmentof diseases and conditions that are ameliorated by the inhibition ofCHK1 kinase function, such as, for example, proliferative conditions,cancer, etc.

Use in Methods of Inhibiting CHK1

One aspect of the present invention pertains to a method of inhibitingCHK1 kinase function, in vitro or in vivo, comprising contacting a CHK1kinase with an effective amount of a BAA compound, as described herein.

One aspect of the present invention pertains to a method of inhibitingCHK1 kinase function in a cell, in vitro or in vivo, comprisingcontacting the cell with an effective amount of a BAA compound, asdescribed herein.

In one embodiment, the method further comprises contacting the cell withone or more other agents selected from: (a) a DNA topoisomerase I or IIinhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TSinhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Suitable assays for determining CHK1 kinase function inhibition aredescribed herein and/or are known in the art.

Use in Methods of Inhibiting Cell Proliferation, Etc.

The BAA compounds described herein, e.g., (a) regulate (e.g., inhibit)cell proliferation; (b) inhibit cell cycle progression; (c) promoteapoptosis; or (d) a combination of one or more of these.

One aspect of the present invention pertains to a method of regulating(e.g., inhibiting) cell proliferation (e.g., proliferation of a cell),inhibiting cell cycle progression, promoting apoptosis, or a combinationof one or more these, in vitro or in vivo, comprising contacting a cellwith an effective amount of a BAA compound, as described herein.

In one embodiment, the method is a method of regulating (e.g.,inhibiting) cell proliferation (e.g., proliferation of a cell), in vitroor in vivo, comprising contacting a cell with an effective amount of aBAA compound, as described herein.

In one embodiment, the method further comprises contacting the cell withone or more other agents selected from: (a) a DNA topoisomerase I or IIinhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TSinhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

In one embodiment, the method is performed in vitro.

In one embodiment, the method is performed in vivo.

In one embodiment, the BAA compound is provided in the form of apharmaceutically acceptable composition.

Any type of cell may be treated, including but not limited to, lung,gastrointestinal (including, e.g., bowel, colon), breast (mammary),ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas,brain, and skin.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound regulates (e.g., inhibits) cell proliferation,etc. For example, assays which may conveniently be used to assess theactivity offered by a particular compound are described herein.

For example, a sample of cells (e.g., from a tumour) may be grown invitro and a compound brought into contact with said cells, and theeffect of the compound on those cells observed. As an example of“effect,” the morphological status of the cells (e.g., alive or dead,etc.) may be determined. Where the compound is found to exert aninfluence on the cells, this may be used as a prognostic or diagnosticmarker of the efficacy of the compound in methods of treating a patientcarrying cells of the same cellular type.

Use in Methods of Therapy

Another aspect of the present invention pertains to a BAA compound, asdescribed herein, for use in a method of treatment of the human oranimal body by therapy.

In one embodiment, the method of treatment comprises treatment with both(i) a BAA compound, as described herein, and (ii) one or more otheragents selected from: (a) a DNA topoisomerase I or II inhibitor; (b) aDNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) amicrotubule targeted agent; and (e) ionising radiation.

Another aspect of the present invention pertains to (a) a DNAtopoisomerase I or II inhibitor, (b) a DNA damaging agent, (c) anantimetabolite or TS inhibitor, or (d) a microtubule targeted agent, asdescribed herein, for use in a method of treatment of the human oranimal body by therapy, wherein the method of treatment comprisestreatment with both (i) a BAA compound, as described herein, and (a) theDNA topoisomerase I or II inhibitor, (b) the DNA damaging agent, (c) theantimetabolite or TS inhibitor, or (d) the microtubule targeted agent.

Use in the Manufacture of Medicaments

Another aspect of the present invention pertains to use of a BAAcompound, as described herein, in the manufacture of a medicament foruse in treatment.

In one embodiment, the medicament comprises the BAA compound.

In one embodiment, the treatment comprises treatment with both (i) amedicament comprising a BAA compound, as described herein, and (ii) oneor more other agents selected from: (a) a DNA topoisomerase I or IIinhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TSinhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Another aspect of the present invention pertains to use of (a) a DNAtopoisomerase I or II inhibitor, (b) a DNA damaging agent, (c) anantimetabolite or TS inhibitor, or (d) a microtubule targeted agent, asdescribed herein, in the manufacture of a medicament for use in atreatment, wherein the treatment comprises treatment with both (i) a BAAcompound, as described herein, and (a) the DNA topoisomerase I or IIinhibitor, (b) the DNA damaging agent, (c) the antimetabolite or TSinhibitor, or (d) the microtubule targeted agent.

Methods of Treatment

Another aspect of the present invention pertains to a method oftreatment comprising administering to a patient in need of treatment atherapeutically effective amount of a BAA compound, as described herein,preferably in the form of a pharmaceutical composition.

In one embodiment, the method further comprises administering to thesubject one or more other agents selected from: (a) a DNA topoisomeraseI or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TSinhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Conditions Treated—Conditions Mediated by CHK1

In one embodiment (e.g., of use in methods of therapy, of use in themanufacture of medicaments, of methods of treatment), the treatment istreatment of a disease or condition that is mediated by CHK1.

Conditions Treated—Conditions Ameliorated by the Inhibition of CHK1Kinase Function

In one embodiment (e.g., of use in methods of therapy, of use in themanufacture of medicaments, of methods of treatment), the treatment istreatment of: a disease or condition that is ameliorated by theinhibition of CHK1 kinase function.

Conditions Treated—Proliferative Conditions and Cancer

In one embodiment (e.g., of use in methods of therapy, of use in themanufacture of medicaments, of methods of treatment), the treatment istreatment of: a proliferative condition.

The term “proliferative condition,” as used herein, pertains to anunwanted or uncontrolled cellular proliferation of excessive or abnormalcells which is undesired, such as, neoplastic or hyperplastic growth.

In one embodiment, the treatment is treatment of: a proliferativecondition characterised by benign, pre-malignant, or malignant cellularproliferation, including but not limited to, neoplasms, hyperplasias,and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers(see below), psoriasis, bone diseases, fibroproliferative disorders(e.g., of connective tissues), pulmonary fibrosis, atherosclerosis,smooth muscle cell proliferation in the blood vessels, such as stenosisor restenosis following angioplasty.

In one embodiment, the treatment is treatment of: cancer.

In one embodiment, the treatment is treatment of: p53 negative cancer.

In one embodiment, the treatment is treatment of: lung cancer, smallcell lung cancer, non-small cell lung cancer, gastrointestinal cancer,stomach cancer, bowel cancer, colon cancer, rectal cancer, colorectalcancer, thyroid cancer, breast cancer, ovarian cancer, endometrialcancer, prostate cancer, testicular cancer, liver cancer, kidney cancer,renal cell carcinoma, bladder cancer, pancreatic cancer, brain cancer,glioma, sarcoma, osteosarcoma, bone cancer, nasopharyngeal cancer (e.g.,head cancer, neck cancer), skin cancer, squamous cancer, Kaposi'ssarcoma, melanoma, malignant melanoma, lymphoma, or leukemia.

In one embodiment, the treatment is treatment of:

-   -   a carcinoma, for example a carcinoma of the bladder, breast,        colon (e.g., colorectal carcinomas such as colon adenocarcinoma        and colon adenoma), kidney, epidermal, liver, lung (e.g.,        adenocarcinoma, small cell lung cancer and non-small cell lung        carcinomas), oesophagus, gall bladder, ovary, pancreas (e.g.,        exocrine pancreatic carcinoma), stomach, cervix, thyroid,        prostate, skin (e.g., squamous cell carcinoma);    -   a hematopoietic tumour of lymphoid lineage, for example        leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell        lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell        lymphoma, or Burkett's lymphoma;    -   a hematopoietic tumor of myeloid lineage, for example acute and        chronic myelogenous leukemias, myelodysplastic syndrome, or        promyelocytic leukemia;    -   a tumour of mesenchymal origin, for example fibrosarcoma or        habdomyosarcoma; a tumor of the central or peripheral nervous        system, for example astrocytoma, neuroblastoma, glioma or        schwannoma;    -   melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma        pigmentoum; keratoctanthoma; thyroid follicular cancer; or        Kaposi's sarcoma.

In one embodiment, the treatment is treatment of solid tumour cancer.

In one embodiment, the treatment is treatment of: lung cancer, breastcancer, ovarian cancer, colorectal cancer, melanoma, or glioma.

The anti-cancer effect may arise through one or more mechanisms,including but not limited to, the regulation of cell proliferation, theinhibition of cell cycle progression, the inhibition of angiogenesis(the formation of new blood vessels), the inhibition of metastasis (thespread of a tumour from its origin), the inhibition of invasion (thespread of tumour cells into neighbouring normal structures), or thepromotion of apoptosis (programmed cell death). The compounds of thepresent invention may be used in the treatment of the cancers describedherein, independent of the mechanisms discussed herein.

Treatment

The term “treatment,” as used herein in the context of treating acondition, pertains generally to treatment and therapy, whether of ahuman or an animal (e.g., in veterinary applications), in which somedesired therapeutic effect is achieved, for example, the inhibition ofthe progress of the condition, and includes a reduction in the rate ofprogress, a halt in the rate of progress, alleviatiation of symptoms ofthe condition, amelioration of the condition, and cure of the condition.Treatment as a prophylactic measure (i.e., prophylaxis) is alsoincluded. For example, use with patients who have not yet developed thecondition, but who are at risk of developing the condition, isencompassed by the term “treatment.”

For example, treatment includes the prophylaxis of cancer, reducing theincidence of cancer, alleviating the symptoms of cancer, etc.

The term “therapeutically-effective amount,” as used herein, pertains tothat amount of a compound, or a material, composition or dosage formcomprising a compound, which is effective for producing some desiredtherapeutic effect, commensurate with a reasonable benefit/risk ratio,when administered in accordance with a desired treatment regimen.

Combination Therapies

The term “treatment” includes combination treatments and therapies, inwhich two or more treatments or therapies are combined, for example,sequentially or simultaneously. For example, the compounds describedherein may also be used in combination therapies, e.g., in conjunctionwith other agents, for example, cytotoxic agents, anticancer agents,etc. Examples of treatments and therapies include, but are not limitedto, chemotherapy (the administration of active agents, including, e.g.,drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as inphotodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy;photodynamic therapy; gene therapy; and controlled diets.

For example, it may be beneficial to combine treatment with a compoundas described herein with one or more other (e.g., 1, 2, 3, 4) agents ortherapies that regulates cell growth or survival or differentiation viaa different mechanism, thus treating several characteristic features ofcancer development.

One aspect of the present invention pertains to a compound as describedherein, in combination with one or more additional therapeutic agents,as described below.

The particular combination would be at the discretion of the physicianwho would select dosages using his common general knowledge and dosingregimens known to a skilled practitioner.

The agents (i.e., the compound described herein, plus one or more otheragents) may be administered simultaneously or sequentially, and may beadministered in individually varying dose schedules and via differentroutes. For example, when administered sequentially, the agents can beadministered at closely spaced intervals (e.g., over a period of 5-10minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart,or even longer periods apart where required), the precise dosage regimenbeing commensurate with the properties of the therapeutic agent(s).

The agents (i.e., the compound described here, plus one or more otheragents) may be formulated together in a single dosage form, oralternatively, the individual agents may be formulated separately andpresented together in the form of a kit, optionally with instructionsfor their use.

Combination Therapies Employing DNA Damaging Agents

As discussed herein, in some embodiments, the BAA compound is employedin combination with (e.g., in conjunction with) with one or more otheragents selected from: (a) a DNA topoisomerase I or II inhibitor; (b) aDNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) amicrotubule targeted agent; and (e) ionising radiation.

When both a BAA compound and one or more other agents are employed, theymay be used (e.g., contacted, administered, etc.) in any order.Furthermore, they may be used (e.g., contacted, administered, etc.)together, as part of a single formulation, or separately, as separateformulations.

For example, in regard to methods of treatment employing both a BAAcompound and one or more other agents, treatment with (e.g.,administration of) the BAA compound may be prior to, concurrent with, ormay follow, treatment with (e.g., administration of) the one or moreother agents, or a combination thereof.

In one embodiment, treatment with (e.g., administration of) a BAAcompound is concurrent with, or follows, treatment with (e.g.,administration of) the one or more other agents.

In one embodiment, the one or more other agents is a DNA topoisomerase Ior II inhibitor; for example, Etoposide, Toptecan, Camptothecin,Irinotecan, SN-38, Doxorubicin, Daunorubicin.

In one embodiment, the one or more other agents is a DNA damaging agent;for example, alkylating agents, platinating agents, or compounds thatgenerate free radicals; for example, Temozolomide, Cisplatin,Carboplatin, Mitomycin C, Cyclophosphamide, BCNU, CCNU, Bleomycin.

In one embodiment, the one or more other agents is an antimetabolite orTS inhibitor; for example, 5-fluorouracil, hydroxyurea, Gemcitabine,Arabinosylcytosine, Fludarabine, Tomudex, ZD9331.

In one embodiment, the one or more other agents is a microtubuletargeted agent; for example, Paclitaxel, Docetaxel, Vincristine,Vinblastine.

In one embodiment, the one or more other agents is ionising radiation(e.g., as part of radiotherapy).

Other Uses

The BAA compounds described herein may also be used as cell cultureadditives to inhibit CHK1 kinase function, e.g., to inhibit cellproliferation, etc.

The BAA compounds described herein may also be used as part of an invitro assay, for example, in order to determine whether a candidate hostis likely to benefit from treatment with the compound in question.

The BAA compounds described herein may also be used as a standard, forexample, in an assay, in order to identify other compounds, other CHK1kinase function inhibitors, other anti-proliferative agents, otheranti-cancer agents, etc.

Kits

One aspect of the invention pertains to a kit comprising (a) a BAAcompound as described herein, or a composition comprising a BAA compoundas described herein, e.g., preferably provided in a suitable containerand/or with suitable packaging; and (b) instructions for use, e.g.,written instructions on how to administer the compound or composition.

In one embodiment, the kit further comprises one or more other agentsselected from: (a) a DNA topoisomerase I or II inhibitor; (b) a DNAdamaging agent; (c) an antimetabolite or TS inhibitor; and (d) amicrotubule targeted agent.

The written instructions may also include a list of indications forwhich the active ingredient is a suitable treatment.

Routes of Administration

The BAA compound or pharmaceutical composition comprising the BAAcompound may be administered to a subject by any convenient route ofadministration, whether systemically/peripherally or topically (i.e., atthe site of desired action).

Routes of administration include, but are not limited to, oral (e.g., byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., byeyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

The Subject/Patient

The subject/patient may be a chordate, a vertebrate, a mammal, aplacental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g.,a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), alagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog),feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig),ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., amonkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g.,gorilla, chimpanzee, orangutang, gibbon), or a human.

Furthermore, the subject/patient may be any of its forms of development,for example, a foetus.

In one preferred embodiment, the subject/patient is a human.

Formulations

While it is possible for the BAA compound to be administered alone, itis preferable to present it as a pharmaceutical formulation (e.g.,composition, preparation, medicament) comprising at least one BAAcompound, as described herein, together with one or more otherpharmaceutically acceptable ingredients well known to those skilled inthe art, including, but not limited to, pharmaceutically acceptablecarriers, diluents, excipients, adjuvants, fillers, buffers,preservatives, anti-oxidants, lubricants, stabilisers, solubilisers,surfactants (e.g., wetting agents), masking agents, colouring agents,flavouring agents, and sweetening agents. The formulation may furthercomprise other active agents, for example, other therapeutic orprophylactic agents.

Thus, the present invention further provides pharmaceuticalcompositions, as defined above, and methods of making a pharmaceuticalcomposition comprising admixing at least one BAA compound, as describedherein, together with one or more other pharmaceutically acceptableingredients well known to those skilled in the art, e.g., carriers,diluents, excipients, etc. If formulated as discrete units (e.g.,tablets, etc.), each unit contains a predetermined amount (dosage) ofthe compound.

The term “pharmaceutically acceptable,” as used herein, pertains tocompounds, ingredients, materials, compositions, dosage forms, etc.,which are, within the scope of sound medical judgment, suitable for usein contact with the tissues of the subject in question (e.g., human)without excessive toxicity, irritation, allergic response, or otherproblem or complication, commensurate with a reasonable benefit/riskratio. Each carrier, diluent, excipient, etc. must also be “acceptable”in the sense of being compatible with the other ingredients of theformulation.

Suitable carriers, diluents, excipients, etc. can be found in standardpharmaceutical texts, for example, Remington's Pharmaceutical Sciences,18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbookof Pharmaceutical Excipients, 5th edition, 2005.

The formulations may be prepared by any methods well known in the art ofpharmacy. Such methods include the step of bringing into association thecompound with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association the compound with carriers (e.g.,liquid carriers, finely divided solid carrier, etc.), and then shapingthe product, if necessary.

The formulation may be prepared to provide for rapid or slow release;immediate, delayed, timed, or sustained release; or a combinationthereof.

Formulations may suitably be in the form of liquids, solutions (e.g.,aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous),emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups,electuaries, mouthwashes, drops, tablets (including, e.g., coatedtablets), granules, powders, losenges, pastilles, capsules (including,e.g., hard and soft gelatin capsules), cachets, pills, ampoules,boluses, suppositories, pessaries, tinctures, gels, pastes, ointments,creams, lotions, oils, foams, sprays, mists, or aerosols.

Formulations may suitably be provided as a patch, adhesive plaster,bandage, dressing, or the like which is impregnated with one or morecompounds and optionally one or more other pharmaceutically acceptableingredients, including, for example, penetration, permeation, andabsorption enhancers. Formulations may also suitably be provided in theform of a depot or reservoir.

The compound may be dissolved in, suspended in, or admixed with one ormore other pharmaceutically acceptable ingredients. The compound may bepresented in a liposome or other microparticulate which is designed totarget the compound, for example, to blood components or one or moreorgans.

Formulations suitable for oral administration (e.g., by ingestion)include liquids, solutions (e.g., aqueous, non-aqueous), suspensions(e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water,water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders,capsules, cachets, pills, ampoules, boluses.

Formulations suitable for buccal administration include mouthwashes,losenges, pastilles, as well as patches, adhesive plasters, depots, andreservoirs. Losenges typically comprise the compound in a flavoredbasis, usually sucrose and acacia or tragacanth. Pastilles typicallycomprise the compound in an inert matrix, such as gelatin and glycerin,or sucrose and acacia. Mouthwashes typically comprise the compound in asuitable liquid carrier.

Formulations suitable for sublingual administration include tablets,losenges, pastilles, capsules, and pills.

Formulations suitable for oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),mouthwashes, losenges, pastilles, as well as patches, adhesive plasters,depots, and reservoirs.

Formulations suitable for non-oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),suppositories, pessaries, gels, pastes, ointments, creams, lotions,oils, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for transdermal administration include gels,pastes, ointments, creams, lotions, and oils, as well as patches,adhesive plasters, bandages, dressings, depots, and reservoirs.

Tablets may be made by conventional means, e.g., compression ormoulding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine thecompound in a free-flowing form such as a powder or granules, optionallymixed with one or more binders (e.g., povidone, gelatin, acacia,sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers ordiluents (e.g., lactose, microcrystalline cellulose, calcium hydrogenphosphate); lubricants (e.g., magnesium stearate, talc, silica);disintegrants (e.g., sodium starch glycolate, cross-linked povidone,cross-linked sodium carboxymethyl cellulose); surface-active ordispersing or wetting agents (e.g., sodium lauryl sulfate);preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate,sorbic acid); flavours, flavour enhancing agents, and sweeteners.Moulded tablets may be made by moulding in a suitable machine a mixtureof the powdered compound moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and may be formulated so asto provide slow or controlled release of the compound therein using, forexample, hydroxypropylmethyl cellulose in varying proportions to providethe desired release profile. Tablets may optionally be provided with acoating, for example, to affect release, for example an enteric coating,to provide release in parts of the gut other than the stomach.

Ointments are typically prepared from the compound and a paraffinic or awater-miscible ointment base.

Creams are typically prepared from the compound and an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example, at least about 30% w/w of a polyhydric alcohol, i.e., analcohol having two or more hydroxyl groups such as propylene glycol,butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycoland mixtures thereof. The topical formulations may desirably include acompound which enhances absorption or penetration of the compoundthrough the skin or other affected areas. Examples of such dermalpenetration enhancers include dimethylsulfoxide and related analogues.

Emulsions are typically prepared from the compound and an oily phase,which may optionally comprise merely an emulsifier (otherwise known asan emulgent), or it may comprises a mixture of at least one emulsifierwith a fat or an oil or with both a fat and an oil. Preferably, ahydrophilic emulsifier is included together with a lipophilic emulsifierwhich acts as a stabiliser. It is also preferred to include both an oiland a fat. Together, the emulsifier(s) with or without stabiliser(s)make up the so-called emulsifying wax, and the wax together with the oiland/or fat make up the so-called emulsifying ointment base which formsthe oily dispersed phase of the cream formulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodiumlauryl sulfate. The choice of suitable oils or fats for the formulationis based on achieving the desired cosmetic properties, since thesolubility of the compound in most oils likely to be used inpharmaceutical emulsion formulations may be very low. Thus the creamshould preferably be a non-greasy, non-staining and washable productwith suitable consistency to avoid leakage from tubes or othercontainers. Straight or branched chain, mono- or dibasic alkyl esterssuch as di-isoadipate, isocetyl stearate, propylene glycol diester ofcoconut fatty acids, isopropyl myristate, decyl oleate, isopropylpalmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branchedchain esters known as Crodamol CAP may be used, the last three beingpreferred esters. These may be used alone or in combination depending onthe properties required. Alternatively, high melting point lipids suchas white soft paraffin and/or liquid paraffin or other mineral oils canbe used.

Formulations suitable for intranasal administration, where the carrieris a liquid, include, for example, nasal spray, nasal drops, or byaerosol administration by nebuliser, include aqueous or oily solutionsof the compound.

Formulations suitable for intranasal administration, where the carrieris a solid, include, for example, those presented as a coarse powderhaving a particle size, for example, in the range of about 20 to about500 microns which is administered in the manner in which snuff is taken,i.e., by rapid inhalation through the nasal passage from a container ofthe powder held close up to the nose.

Formulations suitable for pulmonary administration (e.g., by inhalationor insufflation therapy) include those presented as an aerosol sprayfrom a pressurised pack, with the use of a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.

Formulations suitable for ocular administration include eye dropswherein the compound is dissolved or suspended in a suitable carrier,especially an aqueous solvent for the compound.

Formulations suitable for rectal administration may be presented as asuppository with a suitable base comprising, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols, for example,cocoa butter or a salicylate; or as a solution or suspension fortreatment by enema.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the compound, such carriers as are known inthe art to be appropriate.

Formulations suitable for parenteral administration (e.g., byinjection), include aqueous or non-aqueous, isotonic, pyrogen-free,sterile liquids (e.g., solutions, suspensions), in which the compound isdissolved, suspended, or otherwise provided (e.g., in a liposome orother microparticulate). Such liquids may additional contain otherpharmaceutically acceptable ingredients, such as anti-oxidants, buffers,preservatives, stabilisers, bacteriostats, suspending agents, thickeningagents, and solutes which render the formulation isotonic with the blood(or other relevant bodily fluid) of the intended recipient. Examples ofexcipients include, for example, water, alcohols, polyols, glycerol,vegetable oils, and the like. Examples of suitable isotonic carriers foruse in such formulations include Sodium Chloride Injection, Ringer'sSolution, or Lactated Ringer's Injection. Typically, the concentrationof the compound in the liquid is from about 1 ng/ml to about 10 μg/ml,for example from about 10 ng/ml to about 1 μg/ml. The formulations maybe presented in unit-dose or multi-dose sealed containers, for example,ampoules and vials, and may be stored in a freeze-dried (lyophilised)condition requiring only the addition of the sterile liquid carrier, forexample water for injections, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules, and tablets.

Dosage

It will be appreciated by one of skill in the art that appropriatedosages of the BAA compounds, and compositions comprising the BAAcompounds, can vary from patient to patient. Determining the optimaldosage will generally involve the balancing of the level of therapeuticbenefit against any risk or deleterious side effects. The selecteddosage level will depend on a variety of factors including, but notlimited to, the activity of the particular BAA compound, the route ofadministration, the time of administration, the rate of excretion of theBAA compound, the duration of the treatment, other drugs, compounds,and/or materials used in combination, the severity of the condition, andthe species, sex, age, weight, condition, general health, and priormedical history of the patient. The amount of BAA compound and route ofadministration will ultimately be at the discretion of the physician,veterinarian, or clinician, although generally the dosage will beselected to achieve local concentrations at the site of action whichachieve the desired effect without causing substantial harmful ordeleterious side-effects.

Administration can be effected in one dose, continuously orintermittently (e.g., in divided doses at appropriate intervals)throughout the course of treatment. Methods of determining the mosteffective means and dosage of administration are well known to those ofskill in the art and will vary with the formulation used for therapy,the purpose of the therapy, the target cell(s) being treated, and thesubject being treated. Single or multiple administrations can be carriedout with the dose level and pattern being selected by the treatingphysician, veterinarian, or clinician.

In general, a suitable dose of the BAA compound is in the range of about10 μg to about 250 mg (more typically about 100 μg to about 25 mg) perkilogram body weight of the subject per day. Where the compound is asalt, an ester, an amide, a prodrug, or the like, the amountadministered is calculated on the basis of the parent compound and sothe actual weight to be used is increased proportionately.

Examples

The following examples are provided solely to illustrate the presentinvention and are not intended to limit the scope of the invention, asdescribed herein.

Chemical Synthesis

Liquid Chromatography—Mass spectrometry (LC-MS) Methods

LC-MS (1) analyses were performed on a Micromass ZQ massspectrometer/Waters Alliance 2795 HT HPLC with a Phenomenex Gemini 3 μm,C18, 30 mm×3 mm i.d. column at a temperature of 35° C. using thefollowing solvent gradient and flow rates:

Solvent A: 0.02% Ammonia and 0.063% ammonium formate in water

Solvent B: 0.02% Ammonia and 5% Solvent A in acetonitrile.

0.00 to 2.50 minutes 95% A/5% B to 5% A/95% B (1.2 mL/minute)

2.50 to 2.75 minutes 5% A/95% B (1.2 mL/minute)

2.75 to 3.50 minutes 5% A/95% B (2.0 mL/minute)

3.50 to 3.65 minutes 5% A/95% B to 95% A/5% B (2.0 mL/minute)

3.65 to 4.00 minutes 95% A/5% B (1.2 mL/minute)

UV detection was at 220-400 nm using a Waters 996 photodiode array UVdetector and ionisation was by positive or negative ion electrospray.Molecular weight scan range was 80-1000 amu.

LC-MS (2) analyses were performed on a Micromass ZQ massspectrometer/Waters Alliance 2795 HT HPLC with a Phenomenex Gemini 5 μm,C18, 30 mm×4.6 mm i.d. column at a temperature of 35° C. and a flow rateof 2 mL/minute using the following solvent gradient:

Solvent A: 0.02% Ammonia and 0.063% ammonium formate in water

Solvent B: 0.02% Ammonia and 5% Solvent A in acetonitrile.

0.00 to 4.25min 95% A/5% B to 5% A/95% B

4.25 to 5.80min 5% A/95% B

5.80 to 5.90min 5% A/95% B to 95% A/5% B

5.90 to 7.00nnin 95% A/5% B

UV detection was at 220-400 nm using a Waters 996 photodiode array UVdetector and ionisation was by positive or negative ion electrospray.Molecular weight scan range was 80-1000 amu.

LC-MS (3) analyses were performed on a Micromass LCT/Waters Alliance2795 HPLC system with a Discovery 5 μm, C18, 50 mm×4.6 mm or 30 mm×4.6mm i.d. column from Supelco at a temperature of 22° C. and a flow rateof 1 mL/minute using the following solvent gradient:

Solvent A: Methanol.

Solvent B: 0.1% Formic acid in water.

0.0-0.3 minutes: 10% A/90% B.

0.3-0.6 minutes: 10% A/90% B to 20% A/80% B.

0.6-4.5 minutes: 20% A/80% B to 90% A/10% B.

4.5-5.4 minutes: 90% A/10% B.

5.4-5.7 minutes: 90% A/10% B to 10% A/90%.B.

5.7-6.0 minutes: 10% A/90% B.

UV detection was at 254 nm and ionisation was by positive or negativeion electrospray. Molecular weight scan range was 50-1000 amu.

LC-MS (3B) analyses were performed on a Micromass LCT/Waters Alliance2795 HPLC system with a Phenomenex Gemini 3 μm, C18, 30 mm×4.6 mm i.d.column at a temperature of 30° C. and a flow rate of 1 mL/minute usingthe following solvent gradient:

Solvent A: Methanol.

Solvent B: 0.1% Formic acid in water.

0.0-0.3 minutes: 10% A/90% B.

0.3-0.6 minutes: 10% A/90% B to 20% A/80% B.

0.6-4.5 minutes: 20% A/80% B to 90% A/10% B.

4.5-5.4 minutes: 90% A/10% B.

5.4-5.7 minutes: 90% A/10% B to 10% A/90%.B.

5.7-6.0 minutes: 10% A/90% B.

UV detection was at 254 nm using a Waters 2487 photodiode array UVdetector and ionisation was by positive or negative ion electrospray.Molecular weight scan range was 50-1000 amu.

LC-MS (4) analyses were performed on a Micromass LCT/Waters Alliance2795 HPLC system with a Merck Chromolith SpeedROD RP-18e, 50 mm×4.6 mmcolumn at a temperature of 25° C. and a flow rate of 2 mL/minute usingthe following solvent gradient:

Solvent A: Methanol.

Solvent B: 0.1% Formic acid in water.

0.0-2.25 minutes: 10% A/90% B to 90% A/10% B.

2.25-3.0 minutes: 90% A/10% B.

3.0-3.3 minutes: 90% N 10% B to 10% A/90% B.

3.3-3.5 minutes: 10% A/90% B.

UV detection was at 254 nm using a Waters 2487 photodiode array UVdetector and ionisation was by positive or negative ion electrospray.Molecular weight scan range was 50-1000 amu.

Synthesis 1-A 6-Chloro-N-(pyrazin-2-yl)pyrimidin-4-amine

A mixture of 2-aminopyrazine (230 mg, 2.42 mmol), sodium tert-butoxide(232 mg, 2.42 mmol) and bis(tri-t-butylphosphine)palladium(0) (51 mg,0.1 mmol) in toluene (2 mL) was degassed under a stream of nitrogen over10 min. 4,6-Dichloropyrimidine (300 mg, 2.01 mmol) was added to themixture and the reaction was heated at 80° C. for 2 h. After cooling,the solution was passed through a PS-SH cartridge and the solventremoved in vacuo. The residue was triturated with dichloromethane andthe resulting solid was collected and dried by vacuum filtration to givecrude 6-chloro-N-(pyrazin-2-yl)pyrimidin-4-amine (333 mg) which was usedwithout further purification.

LCMS (2) Rt=1.65 min; m/z (ESI⁺) 208 (MH⁺).

Synthesis 1-BN-(6-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)pyrazin-2-amine(Z-001)

A mixture of 6-chloro-N-(pyrazin-2-yl)pyrimidin-4-amine (20 mg, 0.096mmol), tert-butyl N-(4-piperidinylmethyl)carbamate (41 mg, 0.193 mmol)and triethylamine (27 μL, 0.193 mmol) in 1-methyl-2-pyrrolidinone (1 mL)was heated at 140° C. for 10 minutes using microwave irradiation. Themixture was concentrated in vacuo and the residue purified usingpreparative HPLC. The purified solid was dissolved in dichloromethane (4mL) and treated with trifluoroacetic acid (4 mL) for 1 hour at roomtemperature. The solution was applied to a MP-TsOH SPE cartridge,washed, then eluted with 2N ammonia and concentrated to giveN-(6-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)pyrazin-2-amine (4.4mg, 16%).

¹H NMR (DMSO-d₆, 400MHz) δ 8.83 (d, 1H, J=1.3 Hz), 8.29 (dd, 1H, J=2.8,1.3 Hz), 8.23 (d, 1H, J=1.0 Hz), 8.08 (d, 1H, J=2.8 Hz), 7.17 (d, 1H,J=1.0 Hz), 4.45 (d, 2H, J=10.9 Hz), 2.95 (m, 2H), 2.61 (d, 2H, J=6.7Hz), 1.90 (d, 2H, J=12.3 Hz), 1.74 (m, 1H), 1.21 (m, 3H). LCMS (2)Rt=1.62 min; m/z (ESI⁺) 286 [MH⁺].

The following compounds were prepared in a similar manner to thatdescribed in Synthesis 1, using the appropriate protected or unprotecteddiamines in place of tert-butyl N-(4-piperidinylmethyl)carbamate inSynthesis 1-B.

Synthesis 2 N-(2-Aminoethyl)-N′-pyrazin-2-ylpyrimidine-4,6-diamine(Z-002)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 1, steps 1-A and 1-B.

¹H NMR (MeOD-d₄, 400 MHz) δ 8.69 (br s, 1H), 8.47 (dd, 1H, 1H, J=2.8,1.5 Hz), 8.18 (d, 1H, J=1.0 Hz), 8.06 (d, 1H, J=2.8 Hz), 7.12 (br s,1H), 3.44 (t, 2H, J=6.1 Hz), 2.89 (t, 2H, J=6.1 Hz). LCMS (2) Rt=1.10min; m/z (ESI⁺) 232 (MH⁺).

Synthesis 3 6-(4-Aminopiperidin-1-yl)-N-pyrazin-2-ylpyrimidin-4-amine(Z-003)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 1, steps 1-A and 1-B.

¹H NMR (MeOD-d₄, 400 MHz) δ 8.80 (d, 1H, J=1.3 Hz), 8.27 (dd, 1H, J=2.8,1.5 Hz), 8.21 (d, 1H, J=0.8 Hz), 8.05 (d, 1H, J=2.8 Hz), 7.15 (d, 1H,J=1.0 Hz), 4.37 (d, 2H, J=13.6 Hz), 3.01-2.94 (m, 3H), 1.95-1.91 (m,2H), 1.40-1.29 (m, 2H). LCMS (2) Rt=1.43 min; m/z (ESI⁺) 272 (MH⁺).

Synthesis 4N-(Piperidin-4-ylmethyl)-N′-pyrazin-2-ylpyrimidine-4,6-diamine (Z-004)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 1, steps 1-A and 1-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.7 (br s, 1H), 8.83 (s, 1H), 8.21 (dd, 1H,J=2.5, 1.5 Hz), 8.15 (d, 1H, J=0.8 Hz), 8.08 (d, 1H, J=2.5 Hz), 7.14 (brm, 1H), 6.90 (s, 1H), 3.1 (br m, 2H), 3.0 (br m, 2H), 2.4 (br m, 2H),1.65-1.63 (m, 3H), 1.13-1.03 (m, 2H). LCMS (2) RT=1.36 min; m/z (ESI⁺)286 (MH⁺).

Synthesis 5 N-(3-Aminopropyl)-N′-pyrazin-2-ylpyrimidine-4,6-diamine(Z-005)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 1, steps 1-A and 1-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.84 (d, 1H, J=1.0 Hz), 8.22 (dd, 1H, J=2.5,1.5 Hz), 8.18 (d, 1H, J=1.0 Hz), 8.08 (d, 1H, J=2.5 Hz), 7.31 (br s,1H), 6.90 (s, 1H), 3.35-3.32 (m, 2H), 2.85-2.80 (m, 4H), 1.84-1.77 (m,3H). LCMS (2) Rt=1.31 min; m/z (ESI⁺) 246 (MH⁺).

Synthesis 6 N-(4-Aminobutyl)-N′-pyrazin-2-ylpyrimidine-4,6-diamine(Z-006)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 1, steps 1A and 1B.

LCMS (2) Rt=1.21 min; m/z (ESI⁺) 260 (MH⁺).

Synthesis 7-A 5-(6-Chloropyrimidin-4-ylamino)pyrazine-2-carbonitrile

A mixture of 4,6-dichloropyrimidine (1.00 g, 6.7 mmol),2-amino-5-cyanopyrazine (806 mg, 6.7 mmol) andbis(triphenylphosphine)palladium(II)chloride (94 mg, 0.134 mmol) in dryTHF (24 mL) was degassed under a stream of nitrogen gas for 10 minuteswith stirring. Lithium bis(trimethylsilyl)amide in THF (1M, 7.38 mL,7.4mmol) was added and the mixture was heated at 135° C. for 20 minutesusing microwave irradiation. The reaction mixture was adsorbed ontosilica and purified by flash column chromatography, eluting with 30%ethyl acetate in hexane, to give5-(6-chloropyrimidin-4-ylamino)pyrazine-2-carbonitrile (300 mg, 19%).

LCMS (1) Rt=1.64 min; m/z (ESI⁻) 231.

Synthesis 7-B5-(6-(Piperidin-4-ylmethylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-007)

A mixture of 5-(6-chloropyrimidin-4-ylamino)pyrazine-2-carbonitrile (124mg, 0.533 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (228mg, 1.066 mmol) and triethylamine (150 μL, 1.07 mmol) in1-methyl-2-pyrrolidinone (1 mL) was heated at 145° C. for 15 minutesusing microwave irradiation. The mixture was concentrated in vacuo andthe residue purified by preparative HPLC. The purified solid wasdissolved in dichloromethane (2 mL) and trifluoroacetic acid (3 mL) andwas stirred for 1 hour at room temperature before being applied to aMP-TsOH cartridge. After washing with methanol, the pure product waseluted using 7M ammonia to give5-(6-(piperidin-4-ylmethylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(10.3 mg, 6%).

¹H NMR (DMSO-d₆, 400 MHz) δ 8.79 (br s, 1H), 8.62 (s, 1H), 8.21 (s, 1H),7.14 (br s, 1H), 3.26 (br s, 1H), 3.18 (m, 2H), 2.71(m, 2H), 1.85 (m,4H), 1.30 (m, 3H).

The following compounds were prepared in a similar manner to thatdescribed in Synthesis 7, using the appropriate protected or unprotecteddiamines in place of tert-butyl 4-(aminomethyl)piperidine-1-carboxylatein Synthesis 7-B.

Synthesis 85-(6-(4-Aminopiperidin-1-yl)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-008)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.00 (d, 1H, J=1.3 Hz), 8.82 (d, 1H, J=1.0Hz), 8.33 (s, 1H), 7.16 (s, 1H), 4.21 (br d, 2H, J=13.4 Hz), 3.05-2.91(m, 3H), 1.80 (br d, 2H, J=12.6 Hz), 1.21 (m, 2H). LCMS (2) Rt=1.84 min;m/z (ESI⁺) 297 (MH⁺), (ESI⁻) 295

Synthesis 92-((2-Aminoethyl)(6-(5-cyanopyrazin-2-ylamino)pyrimidin-4-yl)amino)acetamide(Z-009)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.01 (br s, 2H), 9.00 (d, 1H, J=1.5 Hz),8.85 (d, 1H, J=1.5 Hz), 8.77 (br s, 2H), 8.38 (d, 1H, J=0.8 Hz), 8.33(br s, 2H), 8.25 (br s, 1H), 7.09 (s, 1H), 4.03 (s, 2H), 3.78 (t, 2H,J=5.8 Hz), 2.92 (t, 2H, J=6.5 Hz). LCMS (2) Rt=1.30 min; m/z (ESI⁺) 314(MH⁺), (ESI⁻) 312.

Synthesis 10(S)-2-Amino-5-(6-(5-cyanopyrazin-2-ylamino)pyrimidin-4-ylamino)-N-phenylpentanamide(Z-010)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.85 (br s, 1H), 8.77 (s, 1H), 8.22 (s, 1H),7.62 (d, 2H, J=7.5 Hz), 7.54 (s, 1H), 7.30 (t, 2H, J=7.6 Hz), 7.05 (t,1H, J=7.3 Hz), 7.03 (m, 1H), 3.38 (m, 5H), 1.75-1.47 (m, 4H). LCMS (2)Rt=2.11 min; m/z (ESI⁺) 404 (MH⁺), (ESI⁻) 402.

Synthesis 11(S)-2-Amino-N-benzyl-5-(6-(5-cyanopyrazin-2-ylamino)pyrimidin-4-ylamino)pentanamide(Z-011)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.85 (br s, 1H), 8.78 (s, 1H), 8.37 (t, 1H,J=6.1 Hz), 8.23 (s, 1H), 7.53 (br s, 1H), 7.31-7.19 (m, 6H), 7.03 (br s,1H), 4.28 (d, 2H, J=5.8 Hz), 3.21 (m, 3H), 1.69-1.38 (m, 4H). LCMS (2)Rt=2.05 min; m/z (ESI⁺) 418 (MH⁺), 440 (MNa⁺), (ESI⁻) 416.

Synthesis 125-(6-(Piperidin-4-ylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-012)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.84 (br s, 1H), 8.77 (s, 1H), 8.23 (s, 1H),7.48 (br s, 1H), 7.01 (br s, 1H), 3.89 (br s, 1H), 2.96 (d, 2H, J=12.6Hz), 2.54 (m, 2H), 1.79 (d, 2H, J=12.3 Hz), 1.31 (m, 2H). LCMS (2)Rt=1.80 min; m/z (ESI⁺) 297 (MH⁺), (ESI⁻) 295.

Synthesis 13(S)-5-(6-(Piperidin-3-ylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-013)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.84 (br s, 1H), 8.77 (s, 1H), 8.24 (s, 1H),7.41 (br s, 1H), 7.03 (br s, 1H), 3.90 (br s, 1H), 3.07 (d, 1H, J=12.4Hz), 2.84 (d, 1H, J=12.4 Hz), 2.36 (t, 1H, J=12.4 Hz), 1.89 (m, 1H),1.67 (m, 1H), 1.41 (m, 2H). LCMS (2) Rt=1.84 min; m/z (ESI⁺) 297 (MH⁺),(ESI⁻) 295.

Synthesis 145-(6-(2-(Aminomethyl)morpholino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-014)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.00 (d, 1H, J=1.3 Hz), 8.81 (d, 1H, J=1.3Hz), 8.36 (s, 1H), 7.16 (s, 1H), 4.28-4.02 (m, 3H), 3.97 (d, 2H, J=11.6Hz), 3.51 (t, 2H, J=12.1 Hz), 2.98 (t, 1H, J=12.1 Hz), 2.73-2.63 (m,4H). LCMS (2) Rt=1.75 min; m/z (ESI⁺) 313 (MH⁺), (ES⁻) 311.

Synthesis 155-(6-(4-(Amino(phenyl)methyl)piperidin-1-yl)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-015)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

LCMS (2) Rt=2.61 min; m/z (ESI⁺) 387 (MH⁺).

Synthesis 165-(6-(4-Aminobutylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-016)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.86 (br s, 1H), 8.77 (s, 1H), 8.44 (s, 1H),8.24 (s, 1H), 7.57 (br s, 1H), 7.02 (br s, 1H), 3.29 (m, 2H), 2.75 (m,2H), 1.55 (m, 4H). LCMS (2) Rt=1.86 min; m/z (E51⁴) 285 (MH⁺), (ESI⁻)283.

Synthesis 172-((2-Aminoethyl)(6-(5-cyanopyrazin-2-ylamino)pyrimidin-4-yl)amino)-N-benzylacetamide(Z-017)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.82 (br s, 1H), 8.17 (s, 1H), 7.16-6.92 (m,7H), 4.14 (d, 2H, J=5.8 Hz), 4.04 (br s, 3H), 3.34 (m, 4H), 2.69 (t, 2H,J=6.0 Hz). LCMS (2) Rt=2.12 min; m/z (ESI⁺) 404 (MH⁺), 426 (MNa⁺),(ESI⁻) 402.

Synthesis 185-(6-(Piperazin-1-yl)pyrimidin-4-ylamino)pyrazine-2-carbonitrile (Z-018)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (MeOD-d₄, 400 MHz) δ 8.96 (d, 1H, J=1.5 Hz), 8.66 (d, 1H, J=1.5Hz), 8.50 (br s, 1H), 8.39 (d, 1H, J=1.0 Hz), 7.30 (d, 1H, J=1.0 Hz),3.89 (t, 4H, J=5.3 Hz), 3.26 (t, 4H, J=5.3 Hz). LCMS (2) Rt=1.70 min;m/z (ESI⁺) 283 (MH⁺), (ESI⁻) 281.

Synthesis 195-(6-(4-(Aminomethyl)piperidin-1-yl)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-019)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.91 (br s, 1H), 8.88 (m, 2H), 8.47 (s,1H), 8.17 (br s, 3H), 7.16 (s, 1H), 3.75-3.65 (m, 2H), 3.59 (s, 1H),3.09 (t, 2H, J=12.1 Hz), 2.73 (t, 2H, J=5.8 Hz), 1.98 (br s, 1H), 1.88(d, 2H, J=11.9 Hz), 1.26-1.16 (m, 2H). LCMS (2) Rt=2.08 min; m/z (ESI⁺)311 (MH⁺), (ESI⁻) 309.

Synthesis 205-(6-(2-Aminoethylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-020)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.88 (br s, 1H), 8.78 (d, 1H, J=1.3 Hz),8.40 (br s, 1H), 8.27 (s, 1H), 7.84 (br s, 1H), 7.05 (br s, 1H), 3.45(br s, 2H), 2.89 (t, 2H, J=6.1 Hz). LCMS (2) Rt=1.53 min; m/z (ESI⁺) 257(MH⁺), (ESI⁻) 255.

Synthesis 215-(6-(3-Aminopropylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-021)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.63 (br s, 1H), 8.53 (s, 1H), 8.19 (br s,1H), 8.00 (s, 1H), 7.44 (br s, 1H), 6.79 (br s, 1H), 3.10 (3H, br s),2.53 (m, 3H), 1.51 (quin, 2H, J=7.1 Hz). LCMS (2) Rt=1.74 min; m/z(ESI⁺) 271 (MH⁺), (ESI⁻) 269.

Synthesis 225-(6-(Piperidin-3-ylmethylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-022)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.57 (br s, 1H), 8.93-8.78 (m, 4H), 7.28(s, 1H), 3.75 (m, 1H), 3.66 (s, 1H), 3.55 (m, 1H), 3.29 (m, 3H),2.86-2.65 (m, 2H), 2.13 (m, 1H), 1.86 (m, 2H), 1.70 (m, 1H), 1.31 (m,1H). LCMS (2) Rt=2.01 min; m/z (ESI⁺) 311 (MH⁺), (ESI⁻) 309.

Synthesis 235-(6-(4-Amino-4-benzylpiperidin-1-yl)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-023)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.99 (d, 1H, J=1.3 Hz), 8.81 (d, 1H, J=1.5Hz), 8.30 (d, 1H, J=0.8 Hz), 7.31-7.19 (m, 5H), 7.14 (s, 1H), 3.38 (m,4H), 2.66 (s, 2H), 1.49 (m, 2H), 1.35 (m, 2H). LCMS (2) Rt=2.69 min; m/z(ESI⁺) 387 (MH⁺), (ESI⁻) 385.

Synthesis 24(S)-5-(6-(Pyrrolidin-3-ylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-024)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.86 (br s, 1H), 8.77 (d, 1H, J=1.3 Hz),8.38 (s, 1H), 8.28 (s, 1H), 7.90 (br s, 1H), 7.03 (br s, 1H), 4.44 (brs, 1H), 3.24 (m, 1H), 3.17-3.01 (m, 3H), 2.89 (dd, 1H, J=4.0, 11.6 Hz),2.13-2.02 (m, 1H), 1.82-1.74 (m, 1H). LCMS (2) Rt=1.75 min; m/z (ESI⁺)283 (MH⁺), (ESI⁻) 281.

Synthesis 25(R)-2-Amino-5-(6-(5-cyanopyrazin-2-ylamino)pyrimidin-4-ylamino)-N-phenylpentanamide(Z-025)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.85 (br s, 1H), 8.77 (d, 1H, J=1.0 Hz),8.22 (s, 1H), 7.62 (d, 2H, J=7.6 Hz), 7.55 (br s, 1H), 7.30 (t, 2H,J=7.6 Hz), 7.03 (t, 1H, J=7.3 Hz), 3.38 (m, 2H), 1.75-1.51 (m, 5H).

Synthesis 26(S)-2-Amino-4-(6-(5-cyanopyrazin-2-ylamino)pyrimidin-4-ylamino)-N-phenylbutanamide(Z-026)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.85 (br s, 1H), 8.75 (s, 1H); 8.24 (s, 1H),7.63 (d, 2H, J=7.6 Hz), 7.55 (br s, 1H), 7.30 (t, 2H, J=7.6 Hz), 7.04(t, 1H, J=7.6 Hz), 7.03 (br s, 1H), 1.94 (m, 1H), 1.66 (m, 1H), 1.30 (d,1H, J=7.1 Hz), 1.13 (t, 1H, J=6.8 Hz).

Synthesis 275-(6-((1R,3s,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-ylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-027)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (500 MHz, DMSO) δ 1.52-1.64 (4H, m), 1.67-1.75 (2H, m), 1.93-2.01(2H, m), 2.23 (3H, s), 3.14 (2H, broad s), 4.20 (1H, broad s), 6.94 (1H,s), 7.28 (1H, s), 8.22 (1H, s), 8.74 (1H, s), 8.86 (1H, broad s), 10.58(1H, broad s). LCMS (3) Rt 1.59 min; m/z (ESI⁺) 337 (MH⁺).

Synthesis 285-(6-((4-Methylpiperidin-4-yl)methylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-028)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (500 MHz, d₄-MeOD) δ 8.76 (1H, s), 8.61 (1H, s), 8.21 (1H, s),7.20 (1H, s), 3.30-3.45 (2H, m), 2.95-3.10 (2H, m), 2.85-2.95 (2H, m),1.55-1.70 (2H, m), 1.40-1.55 (2H, m), 1.07 (3H, s). LCMS (3) Rt 1.58min; m/z (ESI⁺) 325 (MH⁺).

Synthesis 295-(6-(2-(Piperidin-4-yl)ethylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-029)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (500 MHz, d₄-MeOD) δ 8.80 (1H, s), 8.62 (1H, s), 8.22 (1H, s),7.11 (1H, s), 3.35-3.50 (2H, m), 3.10-3.25 (2H, m), 2.70-2.85 (2H, m),1.80-1.90 (2H, m), 1.50-1.70 (2H, m), 1.15-1.35 (3H, m). LCMS (3) Rt1.58 min; m/z (ESI⁺) 325 (MH⁺).

Synthesis 305-(6-(Pyridin-4-ylmethylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-030)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (500 MHz, DMSO) δ 4.54 (2H, s), 7.12 (1H, broad s), 7.29 (2H, d,J=5.0 Hz), 8.07 (1H, s), 8.23 (1H, s), 8.49 (2H, d, J=5.0 Hz), 8.76 (1H,s), 8.87 (1H, s), 10.68 (1H, s). LCMS (3) Rt 1.58 min; m/z (ESI⁺) 305(MH⁺).

Synthesis 315-(6-(Methyl(piperidin-4-ylmethyl)amino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-031)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (500 MHz, d₄-MeOD) δ 8.92 (1H, s), 8.63 (1H, s), 8.26 (1H, s),7.08 (1H, s), 3.45-3.50 (2H, m), 3.05-3.15 (5H, m), 2.55-2.65 (2H, m),1.90-2.05 (1H, m), 1.65-1.75 (2H, m), 1.20-1.35 (2H, m). LCMS (3) Rt1.52 min; m/z (ESI⁺) 325 (MH⁺).

Synthesis 325-(6-(1-(Piperidin-4-yl)ethylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-032)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 7, steps 7-A and 7-B.

¹H NMR (500 MHz, d₄-MeOD) δ 8.83 (1H, s), 8.61 (1H, s), 8.20 (1H, s),7.10 (1H, s), 3.05-3.15 (2H, m), 2.55-2.65 (2H, m), 1.70-1.90 (2H,m),1.55-1.65 (1H, m), 1.25-1.35 (3H, m), 1.20 (3H, d, J=7.5 Hz). LCMS(3) Rt 1.50 min; m/z (ESI⁺) 325 (MH⁺)

Synthesis 335-(6-((Tetrahydro-2H-pyran-4-yl)methylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-033)

A solution of 5-(6-chloropyrimidin-4-ylamino)pyrazine-2-carbonitrile (20mg, 0.086 mmol), 4-(aminomethyl)tetrahydropyran (18 mg, 0.17 mmol), andtriethylamine (0.02 mL, 0.13 mmol) in MeCN (0.2 mL) was heated to 145°C. for 30 minutes by microwave irradiation. The mixture was cooled andsolvent was removed by evaporation. The crude material was redissolvedin a mixture of dichloromethane (89%), MeOH (10%), 0.88 s.g. NH₃ (1%)and adsorbed onto a solvent-conditioned Trikonex silica chromatographycolumn. Elution with the same solvent mixture gave5-(6-((tetrahydro-2H-pyran-4-yl)methylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrileas a yellow powder (11 mg, 41%).

¹H NMR (500 MHz, DMSO) δ 1.15-1.24 (2H, m), 1.60 (2H, d, J=12.5 Hz),1.73-1.83 (1H, m), 3.15-3.28 (4H, m), 3.84 (2H, dd, J=3.0, 11.0 Hz),7.00 (1H, br s), 7.50 (1H, br s), 8.22 (1H, s), 8.75 (1H, s), 8.86 (1H,br s), 10.59 (1H, br s). LCMS (3) Rt 2.79 min; m/z (ESI⁺) 312 (MH⁺).

The following compounds were prepared in a similar manner to thatdescribed in Synthesis 33, using the appropriate amines in place of4-(aminomethyl)tetrahydropyran.

Synthesis 345-(6-(3-Methoxypropylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-034)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 33.

¹H NMR (500 MHz, DMSO) δ 1.75 (1H, quin, J=6.5 Hz), 3.23 (2H, s), 3.38(2H, t, J=6.5 Hz), 3.51 (3H, s), 6.97 (1H, br s), 7.44 (1H, br s), 8.23(1H, s), 8.76 (1H, s), 8.88 (1H, br s), 10.60 (1H, br s). LCMS (3) Rt2.58 min; m/z (ESI⁺) 286 (MH⁺).

Synthesis 355-(6-(2-(Tetrahydro-2H-pyran-4-yl)ethylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-035)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 33.

¹H NMR (500 MHz, DMSO) δ 1.11-1.26 (2H, m), 1.42-1.50 (2H, m), 1.53-1.64(3H, m), 3.22-3.38 (4H, m), 3.82 (2H, dd, J=3.0, 11.0 Hz), 6.97 (1H, brs), 7.41 (1H, br s), 8.22 (1H, s), 8.75 (1H, s), 8.87 (1H, br s), 10.60(1H, br s). LCMS (3) Rt 3.10 min; m/z (ESI⁺) 326 (MH⁺).

Synthesis 365-(6-((Tetrahydrofuran-2-yl)methylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-036)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 33.

¹H NMR (500 MHz, DMSO) δ 1.51-1.60 (1H, m), 1.74-1.95 (3H, m), 3.32-3.39(2H, m), 3.60-3.66 (1H, m), 3.74-3.81 (1H, m), 3.93-4.01 (1H, m), 7.02(1H, br s), 7.51 (1H, br s), 8.22 (1H, s), 8.75 (1H, s), 8.88 (1H, brs), 10.60 (1H, br s). LCMS (3) Rt 2.73 min; m/z (ESI⁺) 298 (MH⁺).

Synthesis 375-(6-((Tetrahydro-2H-pyran-3-yl)methylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-037)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 33.

¹H NMR (500 MHz, DMSO) δ 1.20-1.28 (1H, m), 1.40-1.50 (1H, m), 1.54-1.61(1H, m), 1.75-1.83 (2H, m), 3.09-3.21 (3H, m), 3.30-3.35 (1H, m),3.68-3.72 (1H, m), 3.76-3.80 (1H. m), 7.00 (1H, br s), 7.47 (1H, br s),8.22 (1H, s), 8.75 (1H, s), 8.86 (1H, br s), 10.60 (1H, s). LCMS (3) Rt2.99 min; m/z (ESI⁺) 312 (MH⁺).

Synthesis 385-(6-((1r,4r)-4-Hydroxycyclohexylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-038)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 33.

¹H NMR (500 MHz, DMSO) δ 1.18-1.29 (4H, m), 1.79-1.91 (4H, m), 3.36-3.43(1H, m), 3.73 (1H, broad s), 4.52 (1H, br s), 6.95 (1H, br s), 7.32 (1H,br s), 8.22 (1H, s), 8.75 (1H, s), 8.85 (1H, br s), 10.59 (1H, s).

LCMS (3) Rt 2.46 min; m/z (ESI⁺) 312 (MH⁺).

Synthesis 395-(6-(1-Hydroxy-2-methylpropan-2-ylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-039)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 33.

¹H NMR (500 MHz, DMSO) δ 1.31 (6H, s), 3.53 (2H, d, J=5.5 Hz), 5.05 (1H,t, J=5.5 Hz), 6.95 (1H, s), 7.06 (1H, d, J=1.0 Hz), 8.22 (1H, d, J=1Hz), 8.74 (1H, d, J=1 Hz), 8.85 (1H, d, J=1 Hz), 10.60 (1H, br s). LCMS(3) Rt 2.62 min; m/z (ESI⁺) 286 (MH⁺).

Synthesis 405-(6-(3-Hydroxypropylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-040)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 33.

¹H NMR (500 MHz, DMSO) δ 1.67 (2H, dt, J=6.5, 7.0 Hz), 3.30 (2H,partially obscured by H₂O), 3.47 (2H, t, J=6.5 Hz), 4.46 (1H, br s),6.97 (1H, br s), 7.41 (1H, br s), 8.23 (1H, s), 8.76 (1H, s), 8.88 (1H,br s), 10.61 (1H, br s). LCMS (3) Rt 2.03 min; m/z (ESI⁺) 272 (MH⁺).

Synthesis 415-(6-(4-Hydroxybutylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-041)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 33.

¹H NMR (500 MHz, DMSO) δ 1.46 (2H, dt, J=6.5, 7.0 Hz), 1.54 (2H, dt,J=6.5, 7.0 Hz), 3.26 (2H, br s), 3.41 (2H, t, J=6.5 Hz), 4.37 (1H, brs), 6.97 (1H, br s), 7.42 (1H, br s), 8.22 (1H, s), 8.75 (1H, s), 8.87(1H, br s), 10.59 (1H, br s). LCMS (3) Rt 2.22 min; m/z (ESI⁺) 286(MH⁺).

Synthesis 425-(6-(1,3-Dihydroxypropan-2-ylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-042)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 33.

LCMS (3) Rt 1.61 min; m/z (ESI⁺) 288 (MH⁺).

Synthesis 435-(6-(4-(Hydroxymethyl)piperidin-1-yl)pyrimidin-4-ylamino)pyrazine-2-carbonitrile(Z-043)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 33.

¹H NMR (500 MHz, CDCl₃) δ 1.26 (2H, dq, J=4.0, 12.5 Hz), 1.81-1.94 (4H,m), 2.97 (2H, td, J=2.5, 12.0 Hz), 3.57 (2H, d, J=6.0 Hz), 4.48 (2H, d,J=12.0 Hz), 7.16 (1H, s), 8.37 (1H, s), 8.54 (1H, d, J=1.0 Hz), 8.72(1H, d, J=1.0 Hz), 9.09 (1H, br s). LCMS (3) Rt 2.61 min; m/z (ESI⁺) 312(MH⁺).

Synthesis 44-A tert-Butyl4-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate

A solution of 4-(aminomethyl)-1-boc-piperidine (370 mg, 1.73 mmol) inacetonitrile (1 mL) was added over 1 minute to a solution of2-bromo-4-chloro-5-nitropyridine (373 mg, 1.57 mmol) and triethylamine(0.24 mL, 1.73 mmol) in acetonitrile (5 mL). The solution was stirredfor 30 minutes then partitioned between dichloromethane and water. Theaqueous phase was extracted with dichloromethane (×3) and the combinedorganic phases were dried (Na₂SO4) and concentrated to give tert-butyl4-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate asa light brown foam (640 mg, 98%) which was used without furtherpurification.

¹H NMR (MeOD, 400 MHz) δ 8.82 (s, 1H), 7.25 (s, 1H), 4.14 (m, 3H), 3.35(s, 1H), 1.97-1.88 (m, 1H), 1.80 (m, 3H), 1.27-1.17 (m, 3H). LCMS (1)Rt=2.35 min; m/z (ESI⁺) 415, 417 (MH⁺).

Synthesis 44-B tert-Butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate

Palladium(II)acetate (32 mg, 0.14 mmol) was added to(±)-2,2″-bis(diphenylphosphino)-1,1″-binaphthalene (268 mg, 0.4 mmol) inDMF/toluene (1/1) and the resulting mixture was degassed under a streamof nitrogen gas for 10 minutes. 2-Amino-5-cyanopyrazine (172 mg, 1.43mmol), sodium tert-butoxide (207 mg, 2.15 mmol) and tert-butyl4-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate(595 mg, 1.43 mmol) were added and the mixture was degassed for afurther 5 minutes before being heated at 150° C. for 30 minutes usingmicrowave irradiation. The mixture was concentrated in vacuo andpartially purified by silica chromatography, eluting with 40% ethylacetate-hexane, to give 273 mg of tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylateat a purity of 75% which was used without further purification.

LCMS (1) Rt=2.37 min; m/z (ESI⁻) 453.

Synthesis 44-C tert-Butyl4-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

Tin(II)chloride hydrate (678 mg, 5 eq) was added to a solution oftert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate (273 mg) in ethanol (20 mL). The mixture washeated at 70° C. for 30 minutes then cooled to room temperature andevaporated to dryness. The residue was diluted with ethyl acetate andsaturated aqueous sodium hydrogen carbonate. The suspension was filteredand the aqueous phase was separated and extracted twice with ethylacetate. The combined organic layers were dried (Na₂SO₄) andconcentrated to give crude tert-butyl4-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(233 mg) as a yellow solid.

LCMS (1) Rt 1.94 min; m/z (ESI⁺) 425 (MH⁴), (ESI⁻) 423.

Synthesis 44-D5-(5-Amino-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-001)

Crude tert-butyl4-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(50 mg) was loaded onto a MP-TsOH SPE cartridge, then eluted after 20minutes with 2 M ammonia in methanol. The basic fractions wereconcentrated. Preparative HPLC gave5-(5-amino-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(2.36 mg, 2.4% over 3 steps).

¹H NMR (DMSO-d₅, 400 MHz) δ 8.93 (br s, 1H), 8.63 (d, 1H, J=1.2Hz), 8.34(s, 1H), 7.45 (s, 1H), 6.86 (br s, 1H), 5.70 (m, 1H), 3.18 (m, 2H), 3.01(t, 2H, J=5.6 Hz), 2.67-2.74 (m, 2H), 2.33 (m, 1H), 1.83 (d, 2H, J=11.2Hz), 1.27 (m, 2H). LCMS (2) Rt=1.60 min; m/z (ESI⁺) 325, (ESI⁻) 323.

The following compounds were prepared in a similar manner to thatdescribed in Synthesis 44, using the appropriate protected orunprotected amines in place of 4-(aminomethyl)-1-boc-piperidine in Step44-A.

Synthesis 455-(5-Amino-4-(methylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-002)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A to 44-C.

LCMS (2) Rt=1.51 min; m/z (ESI⁺) 242 (MH⁺), (ESI⁻) 240.

Synthesis 465-(5-Amino-4-(2-aminoethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-003)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A to 44-C.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.03 (br s, 1H), 8.71 (d, 1H, J=1.5Hz), 8.42(s, 2H), 7.58 (s, 1H), 6.92 (br s, 1H), 6.04 (m, 1H), 3.43-3.37 (m, 2H),3.15 (m, 2H). LCMS (2) Rt=1.23 min; m/z (ESI⁺) 271 (MH⁺), (ESI⁻) 269.

Synthesis 475-(5-Amino-4-(2-(dimethylamino)ethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-004)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A to 44-C.

LCMS (2) Rt=1.87 min; m/z (ESI⁺) 299 (MH⁺), (ESI⁻) 297 .

Synthesis 485-(5-Amino-4-(piperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-005)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A to 44-D.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.92 (br s, 1H), 8.62 (d, 1H, J=1.5Hz), 8.29(s, 2H), 7.46 (s, 1H), 6.88 (br s, 1H), 5.40 (m, 1H), 3.25-3.14 (m, 2H),2.89-2.79 (m, 2H), 2.69-2.67 (m, 1H), 2.08-2.00 (m, 2H), 1.57-1.46 (m,2H). LCMS (2) Rt=1.68 min; m/z (ESI⁺) 311 (MH⁺), (ESI⁻) 309.

Synthesis 495-(5-Amino-4-(8-methyl-8-aza-bicyclo[3.2.1]octan-3-ylamino)-pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-006)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A to 44-C.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.98 (br s, 1H), 8.61 (d, 1H, J=1.5 Hz),8.37 (s, 2H), 7.48 (s, 1H), 6.71 (br s, 1H), 5.18 (m, 1H), 3.10 (m, 2H),2.68-2.66 (m, 1H), 2.34-2.31 (m, 1H), 2.23-2.07 (m, 5H), 1.94 (s, 2H),1.79-1.73 (m, 2H), 1.69-1.63 (m, 1H). LCMS (2) Rt=1.92 min; m/z (ESI⁺)351 (MH⁺), (ESI⁻) 349.

Synthesis 505-(5-Amino-4-(1-methylpiperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-007)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A to 44-C.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.97 (br s, 1H), 8.63 (d, 1H, J=1.5 Hz),8.24 (s, 2H), 7.44 (s, 1H), 6.83 (br s, 1H), 5.30 (m, 1H), 2.84-2.77 (m,2H), 2.69-2.66 (m, 1H), 2.20 (s, 2H), 2.09 (s, 3H), 2.07-1.91 (m, 2H),1.52-1.40 (m, 2H). LCMS (2) Rt=1.66 min, m/z (ESI⁺) 325 (MH⁺), (ESI⁻)323.

Synthesis 51(R)-5-(5-Amino-4-(piperidin-3-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-008)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A to 44-D.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.94 (br s, 1H), 8.62 (d, 1H, J=1.3 Hz),8.33 (s, 2H), 7.46 (s, 1H), 6.86 (br s, 1H), 5.36 (m, 1H), 3.38 (m, 2H),3.22-3.17 (m, 1H), 2.93-2.89 (m, 2H), 2.55 (s, 1H), 2.03-1.96 (m, 1H),1.76-1.70 (m, 1H), 1.57-1.41 (m, 2H). LCMS (2) Rt=1.44 min, m/z (ESI⁺)311 (MH⁺), (ESI⁻) 309.

Synthesis 52(S)-5-(5-Amino-4-(piperidin-3-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-009)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A to 44-D.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.80 (br s, 1H), 8.49 (d, 1H, J=1.5 Hz),8.22 (br s, 2H), 7.33 (s, 1H), 6.75 (br s, 1H), 5.32 (d, 1H, J=7.1Hz),3.37-3.30 (m, 1H), 3.13-3.06 (m, 1H), 2.87-2.81 (m, 1H), 2.57-2.50 (m,1H), 2.47-2.40 (m, 1H), 1.89-1.82 (m, 1H), 1.67-1.60 (m, 1H), 1.50-1.30(m, 2H). LCMS (2) Rt=1.67 min, m/z (ESI⁺) 311 (MH⁺), (ESI⁻) 309.

Synthesis 53N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)-2-(dimethylamino)acetamide(Y-010)

Diisopropylethylamine (16 μL, 0.092 mmol), N,N-dimethylglycine (7 mg,0.067 mmol), HOBt (12 mg, 0.092 mmol) and EDC (17 mg, 0.092 mmol) wereadded to tert-butyl4-((5-amino-2-(5-cyanopyrazin-2-ylamino)-pyridin-4-ylamino)-methyp-piperidine-1-carboxylate(26 mg, 0.061 mmol) in DMF (1.5 mL). The mixture was stirred at roomtemperature for 6 hours and then partitioned between dichloromethane andwater. The aqueous phase was extracted with dichloromethane. Thecombined organic layers were dried and concentrated. Preparative HPLCgaveN-(6-(5-cyanopyrazin-2-ylamino)-4-(1-boc-piperidin-4-ylmethylamino)pyridin-3-yl)-2-(dimethylamino)acetamideas a white solid. The solid was dissolved in 20% trifluoroacetic acid indichloromethane. After 20 minutes the mixture was loaded onto a MP-TsOHSPEcartridge and eluted with 2M ammonia in methanol. The basic fractionswere combined and concentrated to giveN-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)-2-(dimethylamino)acetamide(7.52 mg, 30%) as a pale yellow solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.47 (br s, 1H), 9.09 (s, 1H), 9.07 (s,1H), 8.72 (d, 1H, J=1.6 Hz), 7.75 (s, 1H), 7.02 (br s, 1H), 5.95 (t, 1H,J=6.0 Hz), 3.09 (s, 2H), 3.01-2.95 (m, 3H), 2.55 (m, 3H), 2.46-2.41 (m,2H), 2.30 (s, 6H), 1.68 (d, 2H, J=11.2 Hz), 1.13-1.02 (m, 2H). LCMS (2)Rt=1.78 min; m/z (ESI⁺) 410 (MH⁺), (ESI⁻) 408.

The following compounds were prepared in a similar manner to thatdescribed in Synthesis 53 starting from the appropriate4-substituted-5-amino-2-(5-cyanopyrazin-2-ylamino)-pyridine, and usingthe appropriate acid in place of N,N-dimethylglycine.

Synthesis 54N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)-3-(piperidin-1-yl)propanamide(Y-011)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 53.

LCMS (2) Rt=2.64 min; m/z (ESI⁺) 464 (MH⁺), (ESI⁻) 462.

Synthesis 55N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)-3-(4-methoxyphenyl)propanamide(Y-012)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 53.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.45 (br s, 1H), 9.10 (s, 1H), 9.07 (s,1H), 8.71 (d, 1H, J=1.3 Hz), 7.72 (s, 1H), 7.18 (d, 2H, J=8.6 Hz), 6.99(br s, 1H), 6.88 (d, 2H, J=8.6 Hz), 5.74 (t, 1H, J=6.0 Hz), 3.73 (s,3H), 2.99-2.91 (m, 4H), 2.88-2.83 (t, 2H, J=7.2 Hz), 2.64 (t, 2H,J=7.6Hz), 2.47-2.39 (t, 2H, J=11.6 Hz), 1.65 (m, 3H), 1.12-0.99 (m, 2H).LCMS (2) Rt=2.33 min; m/z (ESI⁺) 487 (MH⁺), (ESI⁻) 485.

Synthesis 56N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)-2-(4-methoxyphenypacetamide(Y-013)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 53.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.51 (br s, 1H), 9.37 (s, 1H), 9.06 (s,1H), 8.72 (d, 1H, J=1.5 Hz), 7.77 (s, 1H), 7.28 (m, 2H), 7.03 (br s,1H), 6.90 (m, 2H), 5.88 (t, 1H, J=5.6 Hz), 3.74 (s, 3H), 3.58 (s, 2H),3.17 (s, 1H), 3.02-2.93 (m, 4H), 2.49-2.45 (m, 2H), 1.66 (d, 3H, J=11.4Hz), 1.16-1.04 (m, 2H). LCMS (2) Rt=2.19 min; m/z (ESI⁺) 473 (MH⁺),(ESI⁻) 471.

Synthesis 57N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yI)-4-methoxybenzamide(Y-014)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 53.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.44 (br s, 1H), 9.41 (s, 1H), 9.04 (s,1H), 8.67 (d, 1H, J=1.5 Hz), 7.93 (d, 2H, J=8.8 Hz), 7.73 (s, 1H), 7.01(s, 1H), 6.99 (d, 2H, J=8.8 Hz), 6.18 (t, 1H, J=5.3 Hz), 3.77 (s, 3H),2.89-2.97 (m, 4H), 2.46-2.39 (m, 2H), 1.64 (d, 3H, J=11.4 Hz), 1.05 (m,2H). LCMS (2) Rt=2.17 min; m/z (ES1⁺) 459 (MH⁺), (ESI⁻) 457.

Synthesis 58N-(6-(5-Cyanopyrazin-2-ylamino)-4-(8-methyl-8-aza-bicyclo[3.2.1]octan-3-ylamino)pyridin-3-yl)-2-(dimethylamino)acetamide(Y-015)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 53.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.39 (br s, 1H), 9.08 (br s, 1H), 8.72 (d,1H, J=1.3 Hz), 7.89 (s, 1H), 6.96 (s, 1H), 5.58 (m, 1H), 3.15 (m, 2H),3.11 (s, 2H), 2.31 (s, 6H), 2.24 (s, 3H), 2.20-2.12 (m, 2H), 1.98-1.93(m, 2H), 1.86-1.80 (m, 2H), 1.74-1.69 (m, 2H), 1.57-1.52 (m, 2H). LCMS(2) Rt=1.71 min; m/z (ESI⁺) 436 (MH⁺), (ESI⁻) 434.

Synthesis 59N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-4-ylamino)pyridin-3-yl)-2-(dimethylamino)acetamide(Y-016)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 53.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.49 (br s, 1H), 9.18 (s, 1H), 9.06 (s,1H), 8.74 (d, 1H, J=1.5Hz), 8.36 (s, 1H), 7.85 (s, 1H), 7.12 (br s, 1H),5.60 (m, 1H), 3.15-3.08 (m, 4H), 2.94-2.91 (m, 1H), 2.79-2.70 (m, 2H),2.30 (s, 6H), 2.00-1.93 (m, 2H), 1.51-1.40 (m, 2H). LCMS (2) Rt=1.48min; m/z (ESI⁺) 396 (MH⁺), (ESI⁻) 394.

Synthesis 60N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)acetamide(Y-017)

Triethylamine (11 μL, 0.082 mmol) and acetic anhydride (8 μL, 0.082mmol) were added to a solution of tert-butyl4-((5-amino-2-(5-cyanopyrazin-2-ylamino)-pyridin-4-ylamino)-methylypiperidine-1-carboxylate(29 mg, 0.068 mmol) in DMF (1 mL) at 0° C. After 2 hours, the mixturewas loaded onto a MP-TsOH SPE cartridge, and eluted with 2M ammonia inmethanol. The basic fractions were combined and concentrated. Purifiedby preparative HPLC gaveN-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)acetamide(7.4 mg, 32%).

¹H NMR (DMSO-d₆, 400 MHz) δ 10.51 (br s, 1H), 9.21 (s, 1H), 9.05 (s,1H), 8.74 (d, 1H, J=1.5 Hz), 8.41 (s, 1H), 7.79 (s, 1H), 7.05 (br s,1H), 6.25 (t, 1H, J=6.1 Hz), 3.16 (d, 3H, J=10.4 Hz), 3.04-2.97 (t, 2H,J=6.3 Hz), 2.67 (t, 2H, J=11.4 Hz), 2.04 (s, 3H), 1.79 (d, 2H, J=10.8Hz), 1.32-1.20 (m, 2H). LCMS (2) Rt=1.57 min; m/z (ESI⁺) 367 (MH⁺),(ESI⁻) 365.

Synthesis 61N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)ethanesulfonamide(Y-018)

Triethylamine (15 μL, 0.11 mmol) and ethylsulfonylchloride (8 μL, 0.78mmol) were added to a stirred solution of tert-butyl4-((5-amino-2-(5-cyanopyrazin-2-ylamino)-pyridin-4-ylamino)-methyl)-piperidine-1-carboxylate(30.3 mg, 0.071 mmol) in DMF (1 mL) at 0° C. After 1.5 hours at roomtemperature, further ethylsulfonylchloride (5.5 μL, 0.53 mmol) andtriethylamine (7.5 μL, 0.53 mmol) were added. After 1 hour the reactionmixture was partitioned between dichloromethane and water. The aqueousphase was extracted with dichloromethane. The combined organic phaseswere dried (Na₂SO₄) and concentrated. Preparative HPLC gaveN-(6-(5-cyanopyrazin-2-ylamino)-4-(1-Boc-piperidin-4-ylmethylamino)pyridin-3-yl)ethanesulfonamideas a solid. The material was dissolved in 20% trifluoroacetic acid indichloromethane. After 20 minutes the mixture was loaded onto a MP-TsOHSPE cartridge and eluted with 2M ammonia in methanol. The basicfractions were combined to giveN-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)ethanesulfonamide(2.28 mg, 8%).

¹H NMR (DMSO-d₆, 400 MHz) δ 9.05 (br s, 1H), 8.70 (s, 1H), 7.77 (s, 1H),6.97 (s, 1H), 6.13 (s, 1H), 3.35 (m, 2H), 3.16 (s, 1H), 3.11-2.96 (m,4H), 2.59 (m, 2H), 1.74 (d, 3H, J=10.4 Hz), 1.25-1.14 (m, 5H). LCMS (2)Rt=1.32 min; m/z (ESI⁺) 417 (MH⁺), (ESI⁻) 415.

Synthesis 62-A Methyl4-(0-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloronicotinate

A solution of methyl 4,6-dichloronicotinate (1.20 g, 5.8 mmol),tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.24 g, 5.8 mmol)and triethylamine (4.09 mL, 29.1 mmol) in n-butanol (13 mL) was heatedat 120° C. for 90 minutes by microwave irradiation. The solvent wasevaporated and the mixture was purified by flash chromatography onsilica, eluting with ethyl acetate-hexane (1:4), to give methyl4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloronicotinateas a colourless solid (1.87 g, 84%).

¹H NMR (500 MHz, CDCl₃) δ 1.14-1.27 (3H, m), 1.46 (9H, s) 1.76-1.78 (3H,m), 2.72 (2H, t, J=12.3 Hz), 3.10 (2H, t, J=5.6 Hz), 3.17 (3H, s), 4.16(2H, s), 6.53 1H, s), 8.25 (1H, s), 8.66 (1H, s). LCMS (3) Rt 5.26 min;m/z (ESI⁺) 386, 384 (MH⁺).

Synthesis 62-B Methyl4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)nicotinate

Methyl4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloronicotinate(0.200 g, 0.52 mmol), 4-amino-cyanopyrazine (0.094 g, 0.78 mmol), cesiumcarbonate (0.340 g, 1.04 mmol), Pd₂(dba)₃ (0.021 g, 0.02 mmol) andxantphos (0.024 g, 0.04 mmol) were mixed under an argon atmospherebefore the addition of toluene (3 mL). The reaction mixture was heatedat 130° C. for 30 minutes by microwave irradiation. The cooled mixturewas dissolved in methanol-dichloromethane (1:1). The mixture waspurified by ion exchange chromatography on SCX-II acidic resin (2 g)eluting with methanol, then 2M ammonia-methanol. The basic fractionswere combined and evaporated. Flash column chromatography eluting withethyl acetate-hexane (1:3) gave methyl4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)nicotinateas a yellow solid (0.090 g, 37%).

¹H NMR (500 MHz, CDCl₃) δ 1.19-1.28 (2H, m), 1.41 (9H, s), 1.79-1.82(2H, m), 1.91-1.97 (1H, m), 2.70-2.80 (3H, m), 3.25 (2H, t, J=6.3 Hz),3.86 (3H, s), 4.12-4.14 (2H, m), 6.53 (1H, s), 7.28 (1H, s), 8.23 (1H,t, J=5.3 Hz), 8.62 (1H, s), 8.66 (1H, d, J=1.2 Hz), 9.16 (1H, d, J=1.2Hz) 9.58(1H, s). LCMS (3) Rt 4.37 min; m/z (ESI⁺) 468 (MH⁺).

Synthesis 62-C Methyl6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)-nicotinate(Y-019)

TFA (0.1 mL) was added to a solution of methyl4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)nicotinate(20 mg, 0.04 mmol) in dichloromethane (1 mL) at room temperature. After20 minutes, the solution was evaporated to dryness and purified by ionexchange chromatography on SCX-II acidic resin (500 mg) eluting withmethanol, then 2M ammonia-methanol. The basic fractions were combinedand solvent was evaporated to give methyl6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)-nicotinatecompound as a yellow solid (11 mg, 70%).

¹H NMR (500 MHz, CDCl₃) δ 1.21-1.29 (2H, m), 1.75-1.86 (3H, m),2.05-2.09 (2H, m), 2.55-2.61 (3H, m), 3.04-3.07 (2H, m), 3.20 (2H, t,J=6.3 Hz), 3.87 (3H, s), 7.28 (1H, s), 8.22 (1H, s), 8.64 (1H, d, J=1.2Hz), 8.66 (1H, d, J=1.2 Hz), 9.20(1H, s). LCMS (3) R_(t) 1.50 min; m/z(ESI⁺) 368 (MH⁺).

The following compounds were prepared in a similar manner to thatdescribed in Synthesis 62, using the appropriate protected orunprotected diamines in place of tert-butyl4-(aminomethyl)piperidine-1-carboxylate in Synthesis 62-A.

Synthesis 63 Methyl6-(5-cyanopyrazin-2-ylamino)-4-((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)nicotinate(Y-020))

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A, 62-B and 62-C.

¹H NMR (500 MHz, d₄-MeOD) δ 1.80 (2H, t, J=11.7 Hz), 2.06-2.08 (2H, m),2.25-2.28 (2H, m), 2.35-2.37 (2H, m), 2.61 (3H, s), 3.32 (2H, dt, J=3.2,1.6 Hz), 3.68 (2H, s), 3.87 (3H, s), 3.95-4.01 (1H, m), 7.42 (1H, s),8.60 (1H, d, J=1.3 Hz), 8.65 (1H, s), 8.92 (1H, d, J=1.3 Hz). LCMS (3)Rt 1.68 min; m/z (ESI⁺) 394 (MH⁺).

Synthesis 64 Methyl6-(5-cyanopyrazin-2-ylamino)-4-(methyl(piperidin-4-ylmethyl)amino)nicotinate(Y-021)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A, 62-B and 62-C.

¹H NMR (500 MHz, d₄-MeOD) δ 8.92 (1H, s), 8.60 (1H, s), 8.38 (1H, s),7.45 (1H, s), 3.89 (3H, s), 3.30 (2H, d, J=8.3 Hz), 3.10-3.20 (2H, m),2.96 (3H, s), 2.60-2.70 (2H, m), 1.95-2.05 (1H, m), 1.75-1.85 (2H, m),1.15-1.25 (2H, m). LCMS (3) Rt 1.57 min; m/z (ESI⁺) 382 (MH⁺).

Synthesis 65 Methyl6-(5-cyanopyrazin-2-ylamino)-4-(1-(piperidin-4-yl)ethylamino)nicotinate(Y-022)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A, 62-B and 62-C.

¹H NMR (500 MHz, d₄-MeOD) δ 8.91 (1H, s), 8.63 (1H, s), 8.60 (1H, s),8.20 (1H, d, J=9.5 Hz), 7.25 (1H, s), 3.85 (3H, s), 3.50-3.60 (1H, m),3.05-3.20 (2H, m), 2.55-2.70 (2H, m), 1.80-1.90 (1H, m),1.65-1.80 (2H,m), 1.20-1.40 (3H, m), 1.25 (3H, d, J=7.5 Hz). LCMS (3) Rt1.83 min; m/z(ESI⁺) 382 (MH⁺).

Synthesis 66 Methyl6-(5-cyanopyrazin-2-ylamino)-4-(1-methylpiperidin-4-ylamino)nicotinate(Y-023)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A and 62-B.

¹H NMR (500 MHz, DMSO) δ 1.49-1.59 (2H, m), 1.96-2.03 (2H, m), 2.15-2.25(5H, m), 2.22 (3H, s), 2.70 (2H, br s), 3.40 (1H, br s), 3.81 (3H, s),7.28 (1H, s), 7.96 (1H, d, J=7.0 Hz), 8.61 (1H, s), 8.80 (1H, d, J=1.5Hz), 9.01 (1H, d, J=1.5 Hz), 10.75 (1H, s). LCMS (3) Rt 1.38 min; m/z(ESI⁺) 368 (MH⁺).

Synthesis 67 Methyl6-(5-cyanopyrazin-2-ylamino)-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)nicotinate(Y-024)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A and 62-B.

¹H NMR (500 MHz, DMSO) δ 1.12 (6H, s), 1.15 (6H, s), 1.32 (2H, t, J=12.0Hz), 1.93 (2H, d, J=12.0 Hz), 2.23 (3H, s), 3.68-3.78 (1H, m), 3.81 (3H,s), 7.47 (1H, s), 7.83 (1H, d, J=7.0 Hz), 8.61 (1H, s), 8.66 (1H, d,J=1.5 Hz), 8.89 (1H, d, J=1.5 Hz), 10.87 (1H, s). LCMS (3) Rt 1.99 min;m/z (ESI⁺) 424 (MH⁺).

Synthesis 68 Methyl6-(5-cyanopyrazin-2-ylamino)-4-(2-(piperidin-4-yl)ethylamino)nicotinate(Y-025)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A, 62-B and 62-C.

¹H NMR (500 MHz, MeOD) δ 8.88 (1H, s), 8.62 (1H, s), 8.60 (1H, s), 7.24(1H, s), 3.87 (3H, s), 3.30-3.38 (2H, m), 3.05-3.15 (2H, m), 2.64-2.72(2H, m), 1.80-1.86 (2H, m), 1.60-1.70 (3H, m), 1.20-1.35 (2H, m). LCMS(3) Rt 1.78 min; m/z (ESI⁺) 382 (ME⁺).

Synthesis 69 Methyl6-(5-cyanopyrazin-2-ylamino)-4-((4-methylpiperidin-4-yl)methylamino)nicotinate(Y-026)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A, 62-B and 62-C.

¹H NMR (500 MHz, MeOD) δ 8.90 (1H, s), 8.65 (1H, s), 8.60 (1H, s), 7.35(1H, s), 3.89 (3H, s), 3.2-3.25 (2H, m), 2.95-3.10 (4H, m), 1.53-1.74(4H, m), 1.16 (3H, s). LCMS (3) Rt 1.81 min; m/z (ESI⁺) 382 (MH⁺).

Synthesis 70 Methyl6-(5-cyanopyrazin-2-ylamino)-4-((1-methylpiperidin-4-yl)methylamino)nicotinate(Y-027)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A and 62-B.

¹H NMR (500 MHz, MeOD) δ 8.92 (1H, s), 8.65 (1H, s), 8.64 (1H, s), 7.29(1H, s), 3.89 (3H, s), 3.23-3.30 (2H, m), 3.12-3.23 (2H, m), 2.52 (3H,s), 2.36-2.48 (2H, m), 1.83-2.00 (3H, m), 1.40-1.57 (2H, m). LCMS (3) Rt1.50 min; m/z (ESI⁺) 382 (MH⁺).

Synthesis 71 Methyl6-(5-cyanopyrazin-2-ylamino)-4-((2S,4S)-2-(phenylcarbamoyl)piperidin-4-ylamino)nicotinate(Y-028)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A, 62-B and 62-C.

¹H NMR (500 MHz, DMSO) δ 10.78 (NH, br s), 9.67 (NH, s), 9.02 (1H, s),8.85 (1H, s), 8.63 (1H, s), 7.92 (NH, d, J=7 Hz), 7.66 (2H, d, J=8.5Hz), 7.37 (1H, s), 7.30 (2H, t, J=8.5 Hz), 7.05 (1H, t, J=7.0 Hz), 3.82(3H, s), 3.52-3.62 (1H, m), 3.40-3.45 (1H, m), 3.28 (NH, s), 3.12-3.20(1H, m), 2.70-2.80 (1H, m), 2.30-2.40 (1H, m), 1.98-2.05 (1H, m),1.32-1.45 (2H, m). LCMS (3) Rt 2.54 min; m/z (ESI⁺) 473 (MH⁺).

Synthesis 72 Methyl4-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-ylamino)-6-(5-cyanopyrazin-2-ylamino)nicotinate(Y-029)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A and 62-B.

¹H NMR (500 MHz, CDCl₃) δ 1.68-1.85 (4H, m), 1.98-2.03 (2H, m),2.20-2.22 (2H, m), 3.36 (2H, s), 3.64 (2H, s), 3.78-3.84 (1H, m), 3.88(3H, s), 7.23-7.44 (6H, m), 8.10 (1H, d, J=7.5), 8.50 (1H, d, J=1.4)8.64 (1H, s), 8.68 (1H, s). LCMS (3) Rt 2.37 min; m/z (ESI⁺) 470 (MH⁺).

Synthesis 73 Methyl4-((1R,3r,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-ylamino)-6-(5-cyanopyrazin-2-ylamino)nicotinate(Y-030)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A and 62-B.

¹H NMR (500 MHz, CDCl₃) δ 1.81 (2H, d, J=13.8), 1.99-2.13 (2H, m),2.17-2.19 (2H, m), 2.31-2.35 (2H, m), 3.27 (2H, s), 3.59 (2H, s), 3.79(1H, q, J=6.5), 3.91 (3H, s), 7.07 (1H, s), 7.26-7.29 (1H, m), 7.35 (2H,t, J=7.5), 7.42-7.41 (2H, m), 8.50 (1H, d, J=1.4), 8.71-8.74 (3H, m).LCMS (3) Rt 2.38 min; m/z (ESI⁺) 470 (MH⁺).

Synthesis 74 Methyl6-(5-cyanopyrazin-2-ylamino)-4-((3-methyloxetan-3-yl)methylamino)nicotinate(Y-031)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A and 62-B.

¹H NMR (500 MHz, DMSO) δ 1.36 (3H, s), 3.42 (2H, d, J=5.5 Hz), 3.82 (3H,s), 4.31 (2H, d, J=6.0 Hz), 4.45 (2H, d, J=6.0 Hz), 7.30 (1H, s), 8.25(1H, t, J=5.5 Hz), 8.60 (1H, s), 8.80 (1H, d, J=1.0 Hz), 9.00 (1H, d,J=1.0 Hz), 10.78 (1H, s). LCMS (3) Rt 2.83 min; m/z (ESI⁺) 355 (MH⁺).

Synthesis 75-A tert-Butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(phenylcarbamoyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

Lithium hydroxide (3 mg, 0.12 mmol) was added to a solution of methyl6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)nicotinate (30mg, 0.06 mmol) in a mixture of tert-butanol and water (2:1, 0.3 mL). Thereaction mixture was stirred for 4 days at room temperature thenacidified to pH 3-4 with 1M HCl and extracted with ethyl acetate. Theorganic extract was dried (Na₂SO₄) and solvent was evaporated. The crudeacid was used in the next step without further purification.Triethylamine (10.0 μL, 0.07 mmol) was added to a solution of the acid(29 mg, 0.06 mmol), aniline (4.8 μL, 0.05 mmol) and TBTU (24 mg, 0.06mmol) in DMF (0.3 mL). The reaction mixture was stirred overnight atroom temperature. The mixture was purified by ion exchangechromatography on SCX-II acidic resin (500 mg) eluting with methanol,then 2M ammonia-methanol. The basic fractions were combined and solventwas evaporated.

Preparative TLC, eluting with ethyl acetate-hexane (1:1) gave tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(phenylcarbamoyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylateas a yellow solid (12 mg, 42%).

¹H NMR (500 MHz, (CD₃)₂CO) δ 1.23-1.30 (3H, m), 1.44 (9H, s), 1.82 (2H,d, J=12.6 Hz), 1.91-1.97 (1H, m), 2.05-2.07 (1H, m), 2.74-2.85 (3H, m),3.23 (2H, t, J=5.9 Hz), 4.13 (2H, d, J=11.1 Hz), 7.13 (1H, t, J=7.7 Hz),7.77 (2H, d, J=7.7 Hz), 8.52 (1H, s), 8.63 (1H, s), 8.67 (1H, s). LCMS(3) R_(t) 4.38 min; m/z (ESI⁺) 529 (MH⁺).

Synthesis 75-B6-(5-Cyanopyrazin-2-ylamino)-N-phenyl-4-(piperidin-4-ylmethylamino)nicotinamide(Y-032)

TFA (0.05 mL) was added to a solution of tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(phenylcarbamoyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(11.0 mg, 0.02 mmol) in dichloromethane (0.5 mL) at room temperature.After 20 minutes, solvent was evaporated and the crude product waspurified by ion exchange on SCX-II acidic resin (500 mg) eluting withmethanol, then 2M ammonia-methanol. The basic fractions were combinedand solvent was evaporated to give6-(5-cyanopyrazin-2-ylamino)-N-phenyl-4-(piperidin-4-ylmethylamino)nicotinamideas a yellow solid (5.6 mg, 63%).

¹H NMR (500 MHz, MeOD) δ 1.32 (1H, d, J=9.5), 1.86 (2H, d, J=9.5), 2.65(2H, dt, J=2.2, 12.5), 3.10-3.17 (4H, m), 3.33 (1H, dt, J=1.6, 3.3),7.14-7.17 (2H, m), 7.38-7.35 (2H, m), 7.63 (2H, d, J=7.5), 8.51 (1H, s),8.61 (1H, d, J=1.4), 9.00 (1H, d, J=1.4). LCMS (3) Rt 1.98 min; m/z(ESI⁺) 429 (MH⁺).

The following compounds were prepared from the appropriate substitutedmethyl nicotinate in a similar manner to that described in Synthesis 75,with the appropriate amine replacing aniline in Synthesis 75A.

Synthesis 766-(5-Cyanopyrazin-2-ylamino)-N-ethyl-4-(piperidin-4-ylmethylamino)nicotinamide(Y-033)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR (500 MHz, MeOD) 1.22 (3H, t, J=7.2), 1.32-1.34 (2H, m), 1.86-1.90(2H, m), 2.68 (2H, t, J=11.3), 3.14-3.16 (4H, m), 3.32 (2H, dt, J=1.6,3.3), 3.37 (2H, q, J=7.2), 7.10 (1H, s), 8.31 (1H, s), 8.59 (1H, d,J=1.3), 8.97 (1H, d, J=1.3). LCMS (3) Rt 1.46 min; m/z (ESI⁺) 381 (MH⁺).

Synthesis 776-(5-Cyanopyrazin-2-ylamino)-N-ethyl-4-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)nicotinamide(Y-034)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, step 75-A.

¹H NMR (500 MHz, MeOD) 1.23 (3H, t, J=7.3), 2.22 (2H, d, J=15.5), 2.41(4H, m), 2.57 (2H, d, J=13.9), 2.85 (3H, s), 3.32 (1H, dt, J=1.6, 3.3)3.40 (2H, q, J=7.2), 7.06 (1H, s), 8.40 (1H, s), 8.49 (1H, s), 8.58 (1H,s), 8.96 (1H, s). LCMS (3) Rt 1.63 min; m/z (ESI⁺) 407 (MH⁺).

Synthesis 78-A 5-Chloro-4-morpholinopyridin-2-amine

A mixture of 4,5-dichloropyridin-2-amine (300 mg, 1.84 mmol) andmorpholine (480 mg, 5.52 mmol) in DMA (3.6 mL) was heated at 200° C. for60 minutes by microwave irradiation. The mixture was purified by ionexchange chromatography on SCX-II acidic resin (2 g) eluting withmethanol, then 2M ammonia-methanol. The basic fractions were combinedand solvent was evaporated. Flash chromatography on silica, eluting withethyl acetate-hexane (1:1) gave 5-chloro-4-morpholinopyridin-2-amine asa colourless solid (347 mg, 88%).

¹H NMR (500 MHz, (CD₃)₂CO) δ 3.07-3.09 (4H, m), 3.76-3.78 (4H, m), 5.39(2H, s), 6.20 (1H, s), 7.78 (1H, s). LCMS (3) Rt 2.60 min; m/z (ESI⁺)252 (MK⁺).

Synthesis 78-B5-(5-Chloro-4-morpholinopyridin-2-ylamino)pyrazine-2-carbonitrile

5-Chloro-4-morpholinopyridin-2-amine (68 mg, 0.31 mmol),4-bromo-cyanopyrazine (30 mg, 0.20 mmol), sodium Pert-butoxide (45 mg,0.47 mmol), Pd(OAc)₂ (3 mg, 0.01 mmol) and BINAP (0.030 g, 0.05 mmol)were mixed under argon atmosphere before addition of mixture of DMF intoluene (2:1, 0.7 mL). The reaction mixture was heated to 140° C. bymicrowave irradiation for 20 minutes. The reaction mixture was purifiedby ion exchange chromatography on SCX-II acidic resin (500 mg) elutingwith methanol, then 2M ammonia-methanol. The basic fractions werecombined and solvent was evaporated. Flash chromoatography on silica,eluting with ethyl acetate-hexane (1:1) gave5-(5-chloro-4-morpholinopyridin-2-ylamino)pyrazine-2-carbonitrile as ayellow solid (20 mg, 20%).

¹H NMR (500 MHz, (CD₃)₂CO) δ 3.14-3.16 (4H, m), 3.76-3.79 (4H, m), 7.52(1H, s), 8.22 (1H, s), 8.77 (1H, s), 9.02 (1H, s), 10.77 (1H, s). LCMS(3) Rt 4.55 min; m/z (ESI⁺) 317 (MH⁺).

Synthesis 78-C5-(4-Morpholino-5-phenylpyridin-2-ylamino)pyrazine-2-carbonitrile(Y-035)

A mixture of5-(5-chloro-4-morpholinopyridin-2-ylamino)pyrazine-2-carbonitrile (50mg, 0.16 mmol), phenylboronic acid (38 mg, 0.31 mmol), sodium carbonate(41 mg, 0.39 mmol) and Bedford catalyst (1 mg, 0.01 mmol) in a mixtureof acetonitrile-water (4:1, 2.5 mL) was heated at 150° C. by microwaveirradiation for 30 minutes. The crude reaction mixture was purified byion exchange chromatography on SCX-II acidic resin (500 mg) eluting withmethanol, then 2M ammonia-methanol. The basic fractions were combinedand solvent was evaporated. Preparative TLC, eluting with ethylacetate-hexane (2:3) gave5-(4-morpholino-5-phenylpyridin-2-ylamino)pyrazine-2-carbonitrile as ayellow solid (16 mg, 28%).

¹H NMR (500 MHz, CDCl₃) δ 2.94-3.00 (4H, m), 3.62-3.67 (4H, m),7.22-7.62 (5H, m), 8.05 (1H, s), 8.52 (1H, s), 8.83 (1H, s), 9.00 (1H,s). LCMS (3) Rt 3.17 min; m/z (ESI⁺) 359 (MH⁺).

Synthesis 79-A 2-amino-5-bromopyrazine

N-Bromosuccinimide (8.98 g, 50 mmol) was added portionwise over 15minutes to a solution of 2-aminopyrazine (4.75 g, 50 mmol) indichloromethane (300 mL) at 0° C. After 45 minutes at 0° C., and 3 hoursat room temperature, the mixture was filtered through Celite and thefiltrate was concentrated. The brown residue was purified by silicachromatography, eluting with 35% then 50% ethyl acetate in hexane, togive 2-amino-5-bromopyrazine (6.41 g, 74%) as a yellow solid.

¹H NMR (CDCl₃, 400 MHz) δ 8.02 (s, 1H), 7.71 (s, 1H), 4.58 (br s, 1H).LCMS (1) Rt=1.05 min; m/z (ESI⁺) 174, 176 (MH⁺).

Synthesis 79-B2-Amino-5-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)pyrazine

2-Amino-5-bromopyrazine (1.50 g, 8.6 mmol) was dissolved in anhydrous,deoxygenated DMF (24.5 mL) with triethylamine (10.5 mL). Copper(I)iodide (0.33 g, 1.7 mmol), tetrakis(triphenylphosphine)-palladium(0)(0.61 g, 0.51 mmol) and tert-butyldimethyl(prop-2-ynyloxy)silane (1.90g, 11.2 mmol) were added and the solution was stirred overnight at 60°C., then cooled and partitioned between water and dichloromethane. Theaqueous phase was extracted with dichloromethane and the combinedorganic phases were dried (Na₂SO₄) and evaporated. The residue waspurified by silica chromatography to give2-amino-5-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)pyrazine (2.06 g,91%) as a brown solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 7.87 (d, 1H, J=1.5 Hz), 7.71 (d, 1H, J=1.5Hz), 6.74 (s, 2H), 4.41 (s, 2H), 0.77 (s, 9H), 0.00 (s, 6H). LCMS (1)Rt=2.29 min; m/z (ESI⁺) 264 (MH⁺).

Synthesis 79-C tert-Butyl4-((6-chloropyrimidin-4-ylamino)methyl)-piperidine-1-carboxylate

4,6-Dichloropyrimidine (284 mg, 1.9 mmol), N-Boc-4-aminomethylpiperidine (409 mg, 1.9 mmol) and potassium carbonate (317 mg, 2.3 mmol)were dissolved in acetonitrile (5 mL) and the solution was heated for 30minutes at 120° C. using microwave irradiation. The reaction mixture waspartitioned between water and dichloromethane and the aqueous phase wasextracted with dichloromethane. The combined organic phases were dried(Na₂SO₄) and evaporated to give tert-butyl4-((6-chloropyrimidin-4-ylamino)methyl)-piperidine-1-carboxylate (656mg, 100%) as a yellow oil which was used without further purification.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.26 (s, 1H), 7.80 (br s, 1H), 6.51 (s, 1H),3.92 (m, 2H), 3.23 (m, 2H), 2.68 (br s, 1H), 2.51 (m, 1H), 1.64 (m, 3H),1.06-0.97 (m, 2H). LCMS (1) Rt=1.94 min; m/z (ESI⁺) 271, 227 (MH⁺),(ESI⁻) 325.

Synthesis 79-D tert-butyl4-((6-(5-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)pyrazin-2-yl-amino)pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate

2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene (56 mg, 0.09 mmol) andpalladium acetate (4 mg, 0.015 mmol) were suspended in 5 mL toluene (5mL) and degassed over 10 minutes under a stream of nitrogen gas.2-Amino-5-(3-(tert-butyldimethyl-silyloxy)prop-1-ynyl)pyrazine (50 mg,0.15 mmol) and tert-butyl4-((6-chloropyrimidin-4-ylamino)methyl)-piperidine-1-carboxylate (40 mg,0.15 mmol), in anhydrous and degassed DMF (500 μL), and sodiumtert-butoxide (46 mg, 0.45 mmol) were added and the reaction mixture washeated at 145° C. for 30 minutes by microwave irradiation. The mixturewas evaporated to dryness. The residue was partitioned between water anddichloromethane and the aqueous phase was extracted withdichloromethane. The combined organic phases were dried (Na₂SO₄) andconcentrated. The residue was redissolved in methanol and filteredthrough a PS—SH column. The filtrate was evaporated to dryness to givecrude tert-butyl4-((6-(5-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)pyrazin-2-yl-amino)pyrimidin-4-ylamino)methyl)piperidine-1-carboxylatewhich was used directly for the next step.

LCMS (1) Rt=2.67 min; m/z (ESI⁺) 554 (MH⁺), (ESI⁻) 552.

Synthesis 79-E3-(5-(6-(piperidin-4-ylmethylamino)pyrimidin-4-ylamino)pyrazin-2-yl)prop-2-yn-1-ol(Z-044)

Crude tert-butyl4-((6-(5-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)pyrazin-2-ylamino)pyrimidin-4-ylamino)-methyl)piperidine-1-carboxylate(0.15 mmol) was dissolved in tetra n-butylammonium fluoride (1M in THF,225 μL). After 30 minutes the solution was evaporated and the residuewas purified by preparative HPLC. The resulting solid was dissolved in30% trifluoroacetic acid in dichloromethane and stirred at roomtemperature for 30 minutes. The mixture was adsorbed onto then MP-TsOHSPE cartridge and eluted with 2M ammonia in methanol. The basicfractions were concentrated to give3-(5-(6-(piperidin-4-ylmethylamino)pyrimidin-4-ylamino)pyrazin-2-yl)prop-2-yn-1-ol(7.8 mg, 7.5% over two steps) as a white solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.15 (br s, 1H), 8.79 (br s, 1H), 8.33 (s,1H), 8.18 (s, 1H), 7.34 (br s, 1H), 6.94 (br s, 1H), 5.47 (s, 1H), 4.33(s, 2H), 3.20-3.10 (m, 2H), 2.92 (d, 2H, J=12 Hz), 2.70 (s, 1H),2.45-2.36 (t, 2H, J=12 Hz), 1.94-1.86 (m, 1H), 1.66-1.53 (m, 2H),1.36-1.28 (m, 1H), 1.08-0.97 (m, 2H). LCMS (2) Rt=1.16 min; m/z (ESI⁺)340 (MH⁺), (ESI⁻) 338.

Synthesis 805-(6-(Piperidin-4-ylmethylamino)pyrimidin-4-ylamino)pyrazine-2-carboxamide(Z-045)

A mixture oftert-butyl-4-((6-(5-cyanopyrazin-2-ylamino)pyrimidin-4-ylamino)methyl)-piperidine-1-carboxylate(0.15 mmol) and trifluoroacetic acid was heated at 82° C. for 4 hours.The solution was evaporated to dryness and the residue was purified bypreparative HPLC to give5-(6-(piperidin-4-ylmethylamino)pyrimidin-4-ylamino)pyrazine-2-carboxamide(7.36 mg, 15%).

¹H NMR (DMSO-d₆, 400 MHz) δ 10.16 (br s, 1H), 8.83 (br s, 1H), 8.78 (s,1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.80 (br s, 1H), 7.42 (br s, 1H), 7.29(t, 1H, J=5.8 Hz), 6.99 (s, 1H), 3.19 (t, 2H, J=5.8 Hz), 3.09 (d, 2H,J=12.0 Hz), 2.66-2.58 (m, 2H), 2.19 (t, 1H, J=7.8 Hz), 1.78-1.70 (m,3H), 1.28-1.15 (m, 2H). LCMS (2) Rt=1.04 min; m/z (ESI⁺) 329, (ESI⁻)327.

Synthesis 81 Methyl6-(5-methylpyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)nicotinate(Y-036)

Methyl4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloronicotinate(90 mg, 0.23 mmol), 5-methylpyrazin-2-amine (38 mg, 0.35 mmol, asdescribed in Itoh et al., 2002), cesium carbonate (153 mg, 0.47 mmol),4,5-bis(diphenyl phosphino)-9,9-dimethylxanthene (11 mg, 8 mol %), andtris(dibenzylidene acetone)dipalladium chloroform complex (10 mg, 4 mol%) were added to an oven-dried microwave reactor vial (2 mL) which wascapped and flushed with nitrogen. Anhydrous toluene (1.35 mL) was addedand nitrogen was bubbled through the stirred solution for 10 minutes.The mixture was heated at 130° C. for 30 minutes by microwaveirradiation. The solution was cooled, diluted withdichloromethane-methanol and adsorbed onto a 2 g (solute SCX-II column.The resin was washed with methanol, then with 2M ammonia in methanol.The basic fractions were concentrated and the residue was purified bypreparative TLC, eluting with 10% methanol-dichloromethane) to givemethyl6-(5-methylpyrazin-2-ylamino)-4-(1-Boc-piperidin-4-ylmethylamino)nicotinate(35 mg) as a light green powder.

LCMS (3) Rt 3.62 min; m/z (ESI⁺) 457 (MH⁺).

The material was dissolved in dichloromethane (1 mL) at 0° C. andtrifluoroacetic acid (8 drops) was added. The temperature was allowed torise to ambient. After 2.5 hours the mixture was adsorbed onto a 2 gIsolute SCX-II column. The resin was washed with methanol, then with 2Mammonia in methanol. The basic fractions were concentrated. PreparativeTLC, eluting with 1% concentrated ammonia-10% methanol-89%dichloromethane, gave methyl6-(5-methylpyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)nicotinate(18 mg, 22% over 2 steps) as a yellow powder.

¹H NMR (500 MHz, DMSO) δ 1.17-1.24 (2H, m), 1.66 (2H, d, J=12 Hz),1.68-1.79 (1H, m), 2.40 (3H, s), 2.48 (2H, t, J=12 Hz), 2.98 (2H, d,J=12 Hz), 3.09 (2H, t, J=6 Hz), 3.22 (1H, t, J=6 Hz), 3.80 (3H, s), 7.11(1H, s), 8.00 (1H, t, J=5.5 Hz), 8.14 (1H, s), 8.54 (1H, s), 8.84 (1H,s), 9.90 (1H, br s). LCMS (3) Rt 1.65 min; m/z (ESI⁺) 357 (MH⁺).

Synthesis 82-A 5-Methoxypyrazin-2-amine

5-Bromopyrazin-2-amine (0.11 g, 0.63 mmol) was dissolved in NaOMe/MeOH(0.23 g Na metal in 10 mL MeOH) and heated by microwave irradiation at140° C. for 7 hours. After evaporation of the solvent, the residue waspurified by preparative TLC, eluting with 30% ethyl acetate-n-hexane, togive 5-methoxypyrazin-2-amine (25 mg, 32%).

¹H NMR (500 MHz, MeOD) δ 7.64 (1H, s), 7.58 (1H, s), 3.85 (3H, s). LCMS(3) Rt 1.75 min; m/z (ESI⁺) 126 (MH⁺).

Synthesis 82-B Methyl6-(5-methoxypyrazin-2-ylamino)-4-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)nicotinate(Y-037)

Methyl6-chloro-4-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)nicotinate (26mg, 0.084 mmol, prepared as described in Synthesis 62 and 63),5-methoxypyrazin-2-amine (16 mg, 0.127 mmol), cesium carbonate (55 mg,0.169 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.9 mg, 7mol %), and tris(dibenzylideneacetone)dipalladium chloroform complex(3.5 mg, 3.5 mol %) were added to a vial which was flushed with nitrogenand sealed. Anhydrous toluene (0.3 mL) and DMF (0.1 mL) were added andnitrogen was bubbled through the stirred solution for 10 minutes. Themixture was heated by microwave irradiation at 130° C. for 30 minutes.The cooled solution was diluted with methanol and adsorbed onto anIsolute SCX-II column. The column was washed with methanol, then with 2Mammonia in methanol. The basic fractions concentrated. Preparative TLC,eluting with ethyl acetate-methanol-concentrated ammonia 10:1:0.2, gavemethyl6-(5-methoxypyrazin-2-ylamino)-4-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)nicotinate(5 mg, 15%) as an oil.

¹H NMR (500 MHz, MeOH) δ 8.56 (1H, s), 8.43 (1H, s), 7.93 (1H, s), 7.00(1H, s), 3.95 (3H, s), 3.84 (3H, s), 3.62-3.70 (2H, m), 2.60 (3H, s),2.20-2.38 (4H, m), 2.00-2.10 (3H, m), 1.73-1.84 (2H, m). LCMS (3) Rt1.70 min; m/z (ESI⁺) 399 (MH⁺).

Synthesis 83-A tert-Butyl4-((2-bromo-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate

N-Boc-4-piperidinemethanol (860 mg, 4.0 mmol) was added to a suspensionof 60% sodium hydride (160 mg, 4.0 mmol) in DMF (40 mmol) at roomtemperature. After 20 minutes, 2-bromo-4-chloro-5-nitropyridine (949 mg,4.0 mmol) was added in one portion, and the resulting mixture wasstirred overnight at room temperature. The mixture was diluted withether and washed with water. The aqueous phase was extracted with ether.The combined organic phases were washed with water and brine, then dried(Na₂SO₄) and concentrated. Silica column chromatography, eluting with20% ethyl acetate-hexane, gave tert-butyl4-((2-bromo-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate (789mg, 62%) as a viscous, pale yellow oil which solidified on standing.

¹H NMR (CDCl₃, 400 MHz) δ 8.80 (s, 1H), 7.20 (s, 1H), 4.05-4.15 (m, 2H),4.00 (d, 2H, J=6.3 Hz), 2.75-2.85 (m, 2H), 2.10 (m, 1H), 1.80-1.90 (m,2H), 1.45 (s, 9H), 1.20-1.30 (m, 2H). LCMS (1) Rt=2.45 min; m/z (ESI⁺)316, 318 (MH⁺),

Synthesis 83-B tert-Butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate

Palladium (II) acetate (14.7 mg, 0.07 mmol) was added to(±)-2,2″-bis(diphenylphosphino)-1,1″-binaphthalene (123 mg, 0.2 mmol) inDMF-toluene (1:1, 5 mL) and the mixture was degassed for 10 minutesunder a stream of nitrogen gas. 2-Amino-5-cyanopyrazine (95 mg, 0.79mmol), sodium-t-butoxide (76 mg, 0.79 mmol) and tert-butyl4-((2-bromo-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate (273mg, 0.67 mmol) were added and the mixture was degassed for a further 5minutes before stirring at room temperature for 2 hours. The mixture waspartitioned between ethyl acetate and water and the aqueous phase wasextracted with ethyl acetate. The combined organic layers were washedwith water and brine, then dried (Na₂SO₄) and concentrated to give crudetert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate(379 mg) which was used without further purification.

LCMS (1) Rt=2.39 min; m/z (ESI⁻) 454.

Synthesis 83-C tert-Butyl4-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-yloxy)methyl)piperidine-1-carboxylate

Tin (II) chloride dihydrate (745 mg, 3.3 mmol) was added to a solutionof crude tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate(301 mg, 0.66 mmol) in ethanol. After heating at 78° C. for 2 hours themixture was cooled to room temperature and concentrated. The residue wasdiluted with ethyl acetate and water and the resulting precipitate wasremoved by filtration. The biphasic filtrate was separated and theaqueous phase was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried (Na₂SO₄) and concentrated to give abrown solid (250 mg). A portion of the crude material was purified bypreparative HPLC to give tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate (16 mg) as a yellow powder.

¹H NMR (CDCl₃, 400 MHz) δ 8.65 (s, 1H), 8.45 (s, 1H), 7.70 (s, 1H), 7.30(s, 1H), 4.15-4.25 (m, 2H), 3.95 (d, 2H, J=6.3 Hz), 3.65 (br s, 2H),2.75-2.80 (m, 2H), 2.00-2.10 (m, 1H), 1.70-1.80 (m, 2H), 1.50 (s, 9H),1.30-1.40 (m, 2H). LCMS (1) Rt=2.05 min, m/z (ESI⁺) 426 (MH⁺), (ESI⁻)424.

Synthesis 83-D5-(5-Amino-4-(piperidin-4-ylmethoxy)pyridin-2-Ylamino)pyrazine-2-carbonitrile(Y-038)

A solution of tert-butyl4-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-yloxy)methyl)piperidine-1-carboxylate(16 mg, 0.038 mmol) in 10 mL dichloromethane (10 mL) was treated over 45minutes with 2 mL trifluoroacetic acid. After concentration of thesolution in vacuo, the required product was isolated by SPE using aMP-TsOH cartridge, eluting with 2N ammonia in methanol. Concentration ofthe eluent gave the required product as a yellow solid (10 mg).

¹H NMR (CDCl₃, 400 MHz) δ 8.45 (s, 1H), 8.40 (s, 1H), 7.65 (s, 1H), 7.30(s, 1H), 3.90 (d, 2H, J=6.4 Hz), 3.60 (br s, 2H), 3.05-3.15 (m, 2H),2.55-2.65 (m, 2H), 1.90-2.00 (m, 1H), 2.70-2.80 (m, 2H), 1.20-1.30 (m,2H). LCMS (2) Rt=1.33 min; m/z (ESI⁻) 324.

Synthesis 84-A tert-Butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(2-(dimethylamino)acetamido)pyridin-4-yloxy)methyl)piperidine-1-carboxylate

1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (95 mg, 0.49 mmol) wasadded to a solution of tert-butyl4-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-yloxy)methyl)piperidine-1-carboxylate(140 mg, 0.33 mmol), N,N-dimethylglycine (51 mg, 0.49 mmol),1-hydroxybenzotriazole hydrate (76 mg, 0.49 mmol) andN-ethyldiisopropylamine (86 μL, 0.49 mmol) in DMF (4 mL). The mixturewas stirred overnight at room temperature then partitioned between ethylacetate and water. The organic phase was washed sequentially with water,dilute sodium bicarbonate solution and brine, then dried (Na₂SO₄) andconcentrated. Preparative HPLC gave tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(2-(dimethylamino)acetamido)pyridin-4-yloxy)methyl)piperidine-1-carboxylate(24 mg, 14%) as an off-white powder.

¹H NMR (CDCl₃, 400 MHz) δ 9.70 (s, 1H), 9.10 (s, 1H), 8.65 (s, 1H), 8.50(s, 1H), 8.00 (br s, 1H), 7.55 (s, 1H), 4.15-4.25 (m, 2H), 4.05 (d, 2H,J=5.90 Hz), 3.15 (s, 2H), 2.75-2.85 (m, 2H), 2.40 (s, 6H), 2.00-2.05 (m,1H), 1.80-1.90 (m, 2H), 1.50 (s, 1H), 1.40-1.50 (m, 2H). LCMS (2)Rt=3.20 min; m/z (ESI⁺) 511 (MH⁺), (ESI⁻) 509.

Synthesis 84-BN-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethoxy)pyridin-3-yl)-2-(dimethylamino)acetamide(Y-039)

A solution of tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(2-(dimethylamino)acetamido)pyridin-4-yloxy)methyl)piperidine-1-carboxylate(24 mg, 0.047 mmol) and trifluoroacetic acid (2 mL) in dichloromethane(10 mL) was stirred for 45 minutes. The solution was concentrated andthe residue was loaded onto a MP-TsOH SPE cartridge. Elution with 2Mammonia in methanol gaveN-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethoxy)pyridin-3-yl)-2-(dimethylamino)acetamideas a yellow solid (14 mg, 72%).

¹H NMR (CDCl₃, 400 MHz) δ 9.70 (s, 1H), 9.20 (s, 1H), 8.65 (s, 1H),8.50, (s, 1H), 7.60 (s, 1H), 4.00 (d, 2H, J=6.6 Hz), 3.15-3.25 (m, 2H),3.15 (s, 1H), 2.70-2.80 (m, 2H), 2.45 (s, 6H), 2.00-2.10 (m, 1H),1.85-1.95 (m, 2H), 1.35-1.45 (m, 2H). LCMS (2) Rt=1.74 min; m/z (ESI⁺)411 (MH⁺), (ESI⁻) 409.

Synthesis 855-(4-(1-Methylpiperidin-4-ylamino)-5-nitropyridin-2-ylamino)pyrazine-2-carbonitrile(Y-040)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A and 44-B.

LCMS (1) Rt=1.88 min; m/z (ESI⁺) 355 (MH⁺).

Synthesis 865-(5-Amino-4-(piperidin-3-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-041)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B, 44-C and 44-D.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.95 (br. s, 1 H), 8.63 (s, 1H), 8.36 (s,2H), 7.45 (s, 1H), 6.83 (br. s, 1H), 5.74 (br. s, 1H) 3.23-3.17 (m, 1H),3.11-2.98 (m, 3H), 2.71-2.60 (m, 2H), 2.02-1.92 (m, 1H), 1.90-1.81 (m,1H), 1.78-1.70 (m, 1 H), 1.59-1.46 (m, 1H), 1.26-1.15 (m, 1H). LC-MS (2)Rt=1.50 min; m/z (ESI⁺) 325 (MH⁺)

Synthesis 875-(5-Amino-4-(3-aminopropylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-042)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B, 44-C and 44-D.

LC-MS (2) Rt=2.57 min; m/z (ESI⁺) 285 (MH⁺).

Synthesis 88(R)—N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-3-ylamino)pyridin-3-yl)-2-(dimethylamino)acetamide(Y-043)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B, and 44-C, and Synthesis 53.

LC-MS (2) Rt=1.67 min; m/z (ESI⁺) 396 (MH⁺).

Synthesis 89N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-2-(dimethylamino)acetamide(Y-044)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B, and 44-C, and Synthesis 53.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.17 (s, 1H), 9.06 (s, 1H), 8.75 (s, 1H),8.35 (s, 2H), 7.77 (s, 1H), 7.05 (br. s, 1H), 6.19-6.16 (m, 1H),3.19-3.16 (m, 1H), 3.13-3.04 (m, 6H), 2.74-2.64 (m, 1H), 2.3 (s, 6H),2.07-1.94 (m, 1H), 1.87-1.71 (m, 2H), 1.59-1.47 (m, 1H), 1.27-1.13 (m,1H). LC-MS (2) Rt=1.82 min; m/z (ESI⁺) 410 (MH⁺).

Synthesis 905-(5-Amino-4-(cyclohexylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-045)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B and 44-C.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.05-8.94 (br. s, 1H), 8.62 (s, 1H), 8.42(s, 1H), 7.44 (s, 2H), 6.85-6.76 (br. s, 1H), 5.30-5.23 (m, 1H),3.26-3.14 (m, 3H—occluded by broad water peak), 2.02-1.98 (m, 1H),1.79-1.74 (m, 1H), 1.68-1.59 (m, 1H), 1.38-1.18 (m, 5H). LC-MS (2)Rt=2.58 min; m/z (ESI⁺) 310 (MH⁺).

Synthesis 91(S)—N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-3-ylamino)pyridin-3-yl)-2-(dimethylamino)acetamide(Y-046)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B, 44-C and 44-D, andSynthesis 53.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.23 (br. s, 1H), 9.07 (s, 1H), 8.72 (s,1H), 8.34 (s, 2H), 7.82 (s, 1H), 7.08 (br. s, 1H), 5.63-5.57 (m, 1H),3.17 (s, 2H), 3.10 (s, 2H), 2.91-2.80 (m, 2H), 2.72-2.57 (m, 1 H), 2.30(s, 6H), 1.92-1.85 (m, 1 H), 1.77-1.64 (m, 1H), 1.56-1.44 (m, 2H). LC-MS(2) Rt=1.74 min; m/z (ESI⁺) 396 (MH⁺).

Synthesis 92(S)-5-(5-Amino-4-(piperidin-3-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-047)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B, 44-C and 44-D.

LC-MS (2) Rt=1.55 min; m/z (ESI⁺) 325 (MH⁺).

Synthesis 93(R)-5-(5-Amino-4-(piperidin-3-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-048)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B, 44-C and 44-D.

LC-MS (2) Rt=1.55 min; m/z (ESI⁺) 325 (MH⁺).

Synthesis 945-(5-Amino-4-(cyclohexylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-049)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B and 44-C.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.00 (br. s, 1H), 8.61 (s, 1H), 8.24 (s,1H), 7.44 (s, 1H), 6.76 (br. s, 1H), 5.61-5.80 (m, 1H), 2.95-2.92 (m,2H), 1.83-1.62 (m, 5H), 1.32-1.18 (m, 4H), 0.97-0.94 (m, 2H). LC-MS (2)Rt=2.79 min; m/z (ESI⁺) 324 (MH⁺).

Synthesis 955-(5-Amino-4-(3-amino-3-phenylpropylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-050)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, 44-A, 44-B, 44-C and 44-D.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.20 (br. s, 1H), 8.94 (br. s, 1H), 8.59(s, 1H), 7.47 (s, 1H), 7.41-7.19 (m, 5H), 6.86-6.79 (br. s, 1H),5.56-5.49 (m, 1H), 4.55-4.40 (br. s, 1H), 3.79 (s, 2H), 3.24-3.17 (m,1H), 2.84-2.77 (m, 1 H). LC-MS (2) Rt=2.16 min; m/z (ESI⁺) 361 (MH⁺).

Synthesis 965-(5-Amino-4-(piperidin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-051)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B, 44-C and 44-D.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.72 (br. s, 1H), 8.38 (s, 1H), 8.11 (s,2H), 7.23 (s, 1H), 6.57 (br. s, 1H), 5.61-5.53 (m, 1H), 2.95-2.81 (m,3H), 2.77-2.66 (m, 1H), 2.46-2.34 (m, 1H), 1.59-1.47 (m, 2H), 1.42-1.32(m, 1H), 1.25-0.97 (m, 3H). LC-MS (2) Rt=1.81 min; m/z (ESI⁺) 325 (MH⁺).

Synthesis 97(S)-2-Amino-5-(5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)-N-phenylpentanamide(Y-052)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B, 44-C and 44-D.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.18 (br. s, 1H), 8.93 (br. s, 1H), 8.61(s, 1H), 7.67-7.59 (m, 2H), 7.45 (s, 1H), 7.35-7.24 (m, 2H), 7.08-7.00(m, 1H), 6.83 (s, 1H), 5.65-5.57 (m, 1H), 4.55-4.40 (m, 2H), 3.20-3.06(m, 3H), 1.84-1.52 (m, 4H). LC-MS (2) Rt=1.98 min; m/z (ESI⁺) 418 (MH⁺).

Synthesis 98N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-3-(piperidin-4-yl)propanamide(Y-053)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B, and 44-C, and Synthesis 53.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.98 (s, 1H), 8.89 (s, 1H), 8.51 (s, 1H),8.28 (s, 1H), 7.60 (s, 1H), 6.77 (s, 1H), 5.91-5.83 (m, 1H), 3.31-3.15(m, 3H), 2.84-2.61 (m, 6H), 2.17-2.00 (m, 3H), 1.62-1.49 (m, 2H),1.49-1.25 (m, 5H), 1.21-1.08 (m, 2H), 0.96-0.80 (m, 3H). LC-MS (2)Rt=1.41 min; m/z (ESI⁺) 464 (MH⁺)

Synthesis 99N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-3-(4-methylthiazol-5-yl)propanamide (Y-054)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B, and 44-C, and Synthesis 53.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.69 (br. s, 1H), 9.37 (br. s, 1H), 9.11 (s,1H), 9.03 (s, 1H), 8.06 (s, 1H), 7.30 (br. s, 1H), 6.58-6.50 (m, 2H),3.50-3.41 (m, 2H), 3.40-3.26 (m, 5H), 2.99-2.87 (m, 3H), 2.62 (s, 3H),2.31-2.18 (m, 1H), 2.14-1.96 (m, 2H), 1.86-1.72 (m, 1H), 1.52-1.40 (m,1H). LC-MS (2) Rt=1.59 min; m/z (ESI⁺) 478 (MH⁺).

Synthesis 100N-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-3-morpholinopropanamide(Y-055)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 44, steps 44-A, 44-B, and 44-C, and Synthesis 53.

LC-MS (2) Rt=1.54 min; m/z (ESI⁺) 466 (MH⁺).

Synthesis 101-A tert-Butyl3-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate

A solution of 3-(aminomethyl)-1-boc-piperidine (409 mg, 1.91 mmol) inacetonitrile (2.5 mL) was added dropwise to a solution of2-bromo-4-chloro-5-nitropyridine (431 mg, 1.82 mmol) and triethylamine(0.28 mL, 2.0 mmol) in acetonitrile (10 mL). The solution was stirredfor 1 hr then partitioned between dichloromethane and water. The aqueousphase was extracted with dichloromethane (×3) and the combined organicphases were dried (Na₂SO₄) and concentrated to give tert-butyl3-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate asa yellow-brown solid (718 mg, 95%) which was used without furtherpurification.

LCMS (1): Rt=2.38 min; m/z (ESI⁺) 415, 417 (MH⁺).

Synthesis 101-B tert-Butyl3-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate

Palladium (II) acetate (39 mg, 0.17 mmol) was added to(±)-2,2″-bis(diphenylphosphino)-1,1″-binaphthalene (321 mg, 0.51 mmol)in DMF/toluene (1/1 15 mL) and the resulting mixture was degassed undera stream of nitrogen gas for 10 min. 2-Amino-5-cyanopyrazine (210 mg,1.7 mmol), sodium tert-butoxide (250 mg, 2.6 mmol) and tert-butyl3-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate(713 mg, 1.7 mmol) were added and the mixture was degassed for a further5 minutes then heated at 150° C. for 30 min using microwave irradiation.The mixture was concentrated in vacuo and water and ethyl acetate wereadded. The aqueous phase was extracted three times with ethyl acetate.The combined organic phases were dried (Na₂SO₄) and concentrated. Theresidue was purified by flash column chromatography on silica, elutingwith a gradient of ethyl acetate in hexane, 10-100% over 50 min. Thefractions containing the product contaminated with2-amino-5-cyanopyrazine were combined, evaporated and repurified bysilica column chromatography, eluting with a gradient of ethyl acetatein hexane, 10-50% over 45 min. Tert-butyl3-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylatewas obtained as a yellow solid (265 mg, 34%).

LCMS (1): Rt=2.38 min; m/z (ESI⁺) 455 (MH⁺).

Synthesis 101-C tert-Butyl3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

tert-Butyl3-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate(265 mg, 0.583 mmol) was dissolved in ethanol (20 mL) and tin (II)chloride hydrate (658 mg, 2.92 mmol) was added. The suspension washeated for 30 min at 70° C. Solvents were removed by evaporation and theresidue was dissolved in ethyl acetate and aqueous saturated sodiumhydrogen carbonate. The mixture was filtered and the residue was washedthoroughly with ethyl acetate. The two phases of the filtrate wereseparated and the aqueous phase was extracted twice with ethyl acetate.The combined organic phases were dried (Na₂SO₄) and solvent was removedby evaporation affording tert-butyl3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(139mg, 56%). The crude product was used directly in the next step.

LCMS (1): Rt=1.97 min; m/z (ESI⁺) 426 (MH⁺).

Synthesis 101-D5-(4-(Piperidin-3-ylmethylamino)-5-(1H-pyrrol-1-yl)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-056)

tent-Butyl3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(121 mg, 0.285 mmol) was dissolved in DCE (6 mL) and2,5-dimethoxytetrahydrofuran (75.3 mg, 0.57 mmol) and acetic acid (2 mL)were added. The solution was heated for 1 h at 80° C. then a furtheraliquot of acetic acid (2 mL) was added. The solution was heated at 80°C. for a further 30 min then cooled to room temperature and partitionedbetween dichloromethane and water. The aqueous phase was extracted withdichloromethane and the combined organic phases were evaporated to givean orange oil. The residue was dissolved in methanol and absorbed onto aTsOH solid phase extraction cartridge, washed once with methanol andallowed to stand for 1 h. The cartridge was then eluted with a solutionof 7M ammonia in methanol and the solution was evaporated to dryness.The residue was purified by HPLC to give5-(4-(piperidin-3-ylmethylamino)-5-(1H-pyrrol-1-yl)pyridin-2-ylamino)pyrazine-2-carbonitrile(4.3 mg, 4%).

¹H NMR (DMSO-d₆, 400 MHz) δ 9.11 (s, 1H), 8.71 (s, 1H), 8.31 (s, 1H),7.82 (s, 1H), 7.14 (s, 1H), 6.86 (s, 2H), 6.29 (s, 1H), 5.44 (m, 1H),3.05-2.86 (m, 3H), 2.51 (m, 1H), 2.31 (m, 1H), 1.86-1.68 (m, 2H),1.66-1.58 (m, 1H), 1.45-1.34 (m, 1H), 1.16-1.05 (m, 1H), LC-MS (2)Rt=2.57 min; m/z (ESI⁺) 375 (MH⁺).

Synthesis 102 (R)-5-(4-(Piperidin-3-ylamino)-5-(1H-pyrrol-1-yl)pyridin-2-ylamino)pyrazine-2-carbonitrile (Y-057)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 101, steps 101-A, 101-B, 101-C and 101-D.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.13 (s, 1H), 8.77 (s, 1H), 8.24 (s, 1H),7.89 (s, 1H), 7.15 (s, 1H), 6.91 (br. s, 2H), 6.30 (br. s, 2H), 5.16 (m,1H), 2.95 (m, 1H), 2.72-2.56 (m, 3H), 1.78-1.38 (m, 4H). LC-MS (2)Rt=2.51 min; m/z (ESI⁺) 361 (MH⁺).

Synthesis 1035-(4-(1-Methylpiperidin-4-ylamino)-5-(1H-pyrrol-1-yl)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-058)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 101, steps 101-A, 101-B, 101-C and 101-D.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.63-10.58 (br. S, 1H), 9.13 (s, 1H), 8.77(s, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 7.19 (s, 1H), 6.90-6.89 (m, 2H),6.31-6.30 (m, 2H), 4.87-4.85 (m, 1H), 2.68-2.64 (m, 2H), 2.17 (s, 3H),2.09-2.04 (m, 2H), 1.91-1.85 (m, 2H), 1.47-1.44 (m, 2H). LC-MS (2)Rt=2.68 min; m/z (ESI⁺) 375 (MH⁺).

Synthesis 1045-(4-(Piperidin-3-ylmethylamino)-5-(pyrrolidin-1-yl)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-059)

tert-Butyl3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(40 mg, 0.094 mmol) (Synthesis 101-C) was dissolved in ethanol (2 mL)and treated with sodium ethoxide (34 mg, 0.509 mmol) and1,4-dibromobutane (44 mg, 0.208 mmol) at between 70 and 80° C. for 96 h.The reaction was quenched with water and the aqueous phase extractedwith dichloromethane. The combined organic phases were evaporated andthe residue was treated with a 20% solution of TFA in dichloromethanefor 20 min. The solution was evaporated and the residue was purified byHPLC to give5-(4-(piperidin-3-ylmethylamino)-5-(pyrrolidin-1-yl)pyridin-2-ylamino)pyrazine-2-carbonitrile(10.3mg, 29%).

LC-MS (2) Rt=2.33 min; m/z (ESI⁺) 379 (MH⁺).

Synthesis 1055-(5-((S)-3-Hydroxypyrrolidin-1-yl)-4-(piperidin-3-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-060)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 104, using (S)-1,4-dibromobutan-2-ol instead of1,4-dibromobutane.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.17 (s, 1H), 8.76 (s, 1H), 8.45 (s, 1H),7.81 (s, 1H), 6.96 (s, 1H), 6.13-6.05 (m, 1H), 4.42-4.32 (m, 1H),3.29-3.17 (m, 3H), 3.16-3.04 (m, 2H), 2.99-2.82 (m, 2H), 2.76-2.64 (m,1H), 2.26-2.13 (m, 1H), 2.11-1.97 (m, 1H), 1.93_1.74 (m, 2H), 1.64-1.49(m, 1H), 1.34-1.18 (m, 1H). LC-MS (2) Rt=1.74 min; m/z (ESI⁺) 395 (MH⁺).

Synthesis 1065-(5-(3-Hydroxypyrrolidin-1-yl)-4-((R)-piperidin-3-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-061)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 105.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.11 (s, 1H), 8.70 (s, 1H), 8.41 (s, 1H),7.76 (s, 1H), 6.90 (s, 1H), 6.09-6.01 (m, 1H), 4.36-4.26 (m, 1H),3.21-3.13 (m, 3H), 3.12-3.00 (m, 2H), 2.92-2.77 (m, 2H), 2.76-2.63 (m,1H), 2.20-1.97 (m, 2H), 1.89-1.70 (m, 2H), 1.62-1.46 (m, 1H), 1.29-1.15(m, 1 H). LC-MS (2) Rt=1.74 min; m/z (ESI⁺) 395 (MH⁺).

Synthesis 107-A tert-Butyl3-((2-(5-cyanopyrazin-2-ylamino)-5-(3-formyl-1H-pyrrol-1-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

tert-Butyl3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(60 mg, 0.141 mmol) (Synthesis 101-C) was dissolved in DCE/AcOH (1/1, 5mL). 2,5-Dimethoxytetrahydrofuran-3-carboxaldehyde (28 uL, 0.211 mmol)was added and the solution was stirred at 80° C. for 1 h. The solutionwas evaporated to dryness and the product (143 mg, approximately 50%purity) was used without further purification.

LC-MS (1) Rt=2.44 min; m/z (ESI⁺) 503 (MH⁺).

Synthesis 107-B tert-Butyl3-((2-(5-cyanopyrazin-2-ylamino)-5-(3-(morpholinomethyl)-1H-pyrrol-1-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

Crude tert-butyl3-((2-(5-cyanopyrazin-2-ylamino)-5-(3-formyl-1H-pyrrol-1-yl)pyridin-4ylamino)methyl)piperidine-1-carboxylate(143 mg of 50% pure material, approx. 0.142 mmol) was dissolved in DCE(1.5 mL) and AcOH (0.15 mL). Morpholine (18.5 uL, 0.213 mmol) and sodiumtriacetoxyborohydride (75 mg, 0.355 mmol) were added and the reactionmixture was stirred at room temperature for 30 min. The reaction mixturewas partitioned between dichloromethane and 10% aqueous NaHCO₃. The twophases were separated and the aqueous phase was extracted withdichloromethane. The combined organic phases were evaporated to drynessand the product (90 mg) was used without further purification.

LC-MS (1) Rt=2.46 min; m/z (ESI⁺) 574 (MH⁺).

Synthesis 107-C5-(5-(3-(Morpholinomethyl)-1H-pyrrol-1-yl)-4-(piperidin-3-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-062)

Crude tert-butyl3-((2-(5-cyanopyrazin-2-ylamino)-5-(3-(morpholinomethyl)-1H-pyrrol-1-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(90 mg) was dissolved in methanol (1 mL) and absorbed onto a TsOH solidphase extraction cartridge and allowed to stand for 2 h. The cartridgewas eluted with 7M ammonia in methanol. The basic fractions wereevaporated to dryness. The crude product was purified by HPLC to give5-(5-(3-(morpholinomethyl)-1H-pyrrol-1-yl)-4-(piperidin-3-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(4.93 mg, 7% over 3 steps).

LC-MS (2) Rt=2.07 min; m/z (ESI⁺) 474 (MH⁺).

Synthesis 1085-(5-(3-(Hydroxymethyl)-1H-pyrrol-1-yl)-4-(piperidin-3-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile (Y-063)

tert-Butyl3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(37 mg, 0.074 mmol) (Synthesis 107-A) was dissolved in methanol (1.5 mL)and cooled to 0° C. Sodium borohydride (15 mg, 0.396 mmol) was added andthe reaction was stirred at 0° C. for 4 h. The solution was evaporatedand the residue was partitioned between water and dichloromethane. Thetwo phases were separated and the aqueous phase was extracted withdichloromethane. The combined organic phases were evaporated and theresidue was dissolved in methanol (1 mL) and absorbed onto a TsOH solidphase extraction cartridge. After 1.5 h the cartridge was eluted with 7Mammonia in methanol. The basic eluent was evaporated to dryness. Theresidue was purified by HPLC to give5-(5-(3-(hydroxymethyl)-1H-pyrrol-1-yl)-4-(piperidin-3-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(3.18 mg, 11%).

¹H NMR (DMSO-d₆, 400 MHz) δ 10.66 (br. s, 1H), 9.13 (s, 1H), 8.78 (s,1H), 8.43 (s, 1H), 7.81 (s, 1H), 7.15 (s, 1H), 6.88-6.79 (m, 1H), 6.27(s, 1H), 5.82-5.73 (m, 1H), 4.29 (s, 2H), 3.27 (s, 2H), 3.06-2.90 (m,2H), 2.39-2.28 (m, 1H), 1.92-1.61 (m, 2H), 1.49-1.35 (m, 1H), 1.16-1.04(m, 1H). LC-MS (2) Rt=2.26 min; m/z (ESI⁺) 387 (MH⁺).

Synthesis 109-A Ethyl 2,5-dimethoxy-2,5-dihydrofuran-3-carboxylate

Ethylfuroate (500 mg, 3.568 mmol) and potassium carbonate (1233 mg, 8.92mmol) were dissolved in methanol (10 mL), cooled to 0° C. Bromine (1140mg, 7.136 mmol) was added dropwise. The reaction mixture was stirred for30 min at 0° C. and was then allowed to warm to room temperature andstirred for an additional 2 h. The reaction mixture was evaporated andthe residue was partitioned between dichloromethane and water. Thephases were separated and the aqueous phase was extracted withdichloromethane. The combined organic phases were dried (Na₂SO₄),filtered and concentrated to give ethyl2,5-dimethoxy-2,5-dihydrofuran-3-carboxylate as a mixture of isomers(659 mg, 91%).

¹H NMR (CDCl₃, 400 MHz) δ 6.83-6.80 (m, 1H), 6.03-5.98 (m, 1H),5.76-5.69 (m, 1H), 4.29 (q, 2H), 3.51 (s), 3.50 (s), 3.47 (s), 3.44 (s,total for previous 4 singlets=6H), 1.33 (t, 3H). LC-MS (1) Rt=1.70 min;no ionisation.

Synthesis 109-B Ethyl 2,5-dimethoxy-tetrahydrofuran-3-carboxylate

Ethyl 2,5-dimethoxy-2,5-dihydrofuran-3-carboxylate (615 mg, 3.044 mmol)was dissolved in methanol (10 mL) and treated with hydrogen (10 bar)over Raney nickel at 40° C. for 2 h. The reaction mixture was evaporatedto dryness to give ethyl 2,5-dimethoxy-tetrahydrofuran-3-carboxylate(564 mg, 91%) which was used directly in the next step.

LC-MS (1) Rt=1.47 min; no ionisation.

Synthesis 109-C tert-Butyl3-((2-(5-cyanopyrazin-2-ylamino)-5-(3-(ethoxycarbonyl)-1H-pyrrol-1-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

tert-Butyl3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(163 mg, 0.384 mmol) (Synthesis 101-C) and ethyl2,5-dimethoxy-tetrahydrofuran-3-carboxylate (196 mg, 0.96 mmol) weredissolved in acetic acid (4 mL) and the solution was stirred at 80° C.for 6.5 h. The reaction mixture was evaporated to dryness and theresidue was used directly in the next step.

LC-MS (1) Rt=3.52 min; m/z (ESI⁺) 547 (MH⁺).

Synthesis 109-D Ethyl1-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylate(Y-064)

tert-Butyl3-((2-(5-cyanopyrazin-2-ylamino)-5-(3-(ethoxycarbonyl)-1H-pyrrol-1-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(3 mg, 0.005 mmol) was dissolved in methanol (1 mL) and absorbed onto aTsOH solid phase extraction cartridge. After 1.5 h the cartridge waseluted with 7M ammonia in methanol. The eluent was evaporated to drynessto give ethyl1-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylate.

LC-MS (1) Rt=1.40 min; m/z (ESI⁺) 447 (MH⁺).

Synthesis 110-A1-(4-((1-(tert-Butoxycarbonyl)piperidin-3-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylicacid

tert-Butyl3-((2-(5-cyanopyrazin-2-ylamino)-5-(3-(ethoxycarbonyl)-1H-pyrrol-1-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(42 mg, 0.077 mmol) was dissolved in ethanol (1 mL). KOH (43 mg, 0.770mmol) was added and the solution was stirred at 50° C. for 72 h. Thereaction mixture was evaporated to dryness and the residue waspartitioned between water and dichloromethane. The two phases wereseparated and the organic phase was extracted with water. The combinedaqueous phases were neutralised to pH 7 by the addition of 1M HCl andthen evaporated to dryness. The product (7 mg, 17%) was used directly inthe next step without further purification.

LC-MS (1) Rt=1.96 min; m/z (ESI⁺) 519 (MH⁺).

Synthesis 110-B1-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylicacid (Y-065)

1-(4-((1-(tert-Butoxycarbonyl)piperidin-3-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylicacid (7 mg, 0.013 mmol) was dissolved in methanol (1 mL) and absorbedonto a TsOH solid phase extraction cartridge cartridge. After 1.5 h thecartridge was eluted with 7M ammonia in methanol. The eluent wasevaporated to dryness to give1-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylic acid.

LC-MS (1) Rt=1.12 min; m/z (ESI⁺) 419 (MH⁺).

Synthesis 111-A tert-butyl3-((5-(3-(2-(tert-butyldimethylsilyloxy)ethylcarbamoyl)-1H-pyrrol-1-yl)-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

1-(4-((1-(tert-Butoxycarbonyl)piperidin-3-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylicacid (80 mg, 0.154 mmol) was dissolved in DMF (1.5 mL).2-(tert-Butyldimethylsilyloxy)ethanamine (41 mg, 0.230 mmol),N-ethyldiisopropylamine (30 mg, 0.230 mmol), 1-hydroxy benzotriazolehydrate (31 mg, 0.230 mmol) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (44 mg, 0.23 mmol) wereadded to the solution and the reaction mixture was stirred for 14 h atroom temperature. The solution was partitioned between dichloromethaneand water. The two phases were separated and the aqueous phase wasextracted with dichloromethane. The combined organic phases were dried(Na₂SO₄) and evaporated to give tert-butyl3-((5-(3-(2-(tert-butyldimethylsilyloxy)ethylcarbamoyl)-1H-pyrrol-1-yl)-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(80 mg, 78%) which was used in the next step without purification.

LC-MS (2) Rt=3.99 min; m/z (ESI⁺) 676 (MH⁺).

Synthesis 111-B1-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-N-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide(Y-066)

tert-Butyl3-((5-(3-(2-(tert-butyldimethylsilyloxy)ethylcarbamoyl)-1H-pyrrol-1-yl)-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(80 mg, 0.118 mmol) was dissolved in THF (2 mL) and tetrabutylammoniumfluoride on silica (1.5 mmol/g; 237 mg, 0.355 mmol) was added. Thereaction mixture was stirred for 1 h at room temperature. The mixturewas filtered and the solvent was evaporated. The residue was dissolvedin methanol (1 mL) and absorbed on to a TsOH solidphase extractioncartridge. After 1.5 h the cartridge was eluted with 7M ammonia inmethanol. The eluent was evaporated to dryness and the residue waspurified by HPLC to give1-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-N-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide.

LC-MS (2) Rt=1.67 min; m/z (ESI⁺) 462 (MH⁺).

Synthesis 1121-(6-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-1H-pyrrole-3-carboxamide(Y-067)

The title compound was prepared using methods analogous to thosedescribed in Synthesis Y-111, steps 111-A and 111-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.11 (s, 1H), 8.78 (s, 1H), 8.38 (s, 1H),7.98-7.90 (m, 1H), 7.84 (s, 1H), 7.37 (s, 1H), 7.18 (s, 1H), 6.85 (s,1H), 6.70 (s, 1H), 6.08-5.99 (m, 1H), 3.49-3.42 (m, 2H), 3.32-3.24 (m,2H), 3.18 (s, 2H), 3.12-2.95 (m, 3H), 2.65-2.55 (m, 1H), 2.44-2.32 (m,1H), 1.99-1.85 (m, 1H), 1.82-1.59 (m, 3H), 1.53-1.40 (m, 1H), 1.20-1.06(m, 1H).

LC-MS (2) Rt=1.71 min; m/z (ESI⁺) 476 (MH⁺).

Synthesis 113N-(6-(5-Cyanopyrazin-2-ylamino)-4-((tetrahydrofuran-3-yl)methoxy)pyridin-3-yl)-3-(piperidin-4-yl)propanamide(Y-068)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 83, steps 83-A, 83-B and 83-C, and Synthesis 84,steps 84-A and 84-B.

LC-MS (2) Rt=1.68 min; m/z (ESI⁺) 452 (MH⁺).

Synthesis 114N-(6-(5-Cyanopyrazin-2-ylamino)-4-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-yl)-3-(piperidin-4-yl)propanamide(Y-069)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 83, steps 83-A, 83-B and 83-C, and Synthesis 84,steps 84-A and 84-B.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.18 (s, 1H), 9.03 (s, 1H), 8.77 (s, 1H),8.43-8.38 (m, 2H), 7.52 (s, 1H), 3.97-3.87 (m, 4H), 3.39-3.29 (m, 4H),3.19-3.10 (m, 2H), 2.73-2.64 (m, 2H), 2.43-2.32 (m, 2H), 2.13-2.02 (m,1H), 1.79-1.67 (m, 3H), 1.58-1.25 (m, 4H), 1.27-1.14 (m, 2H). LC-MS (2)Rt=1.79 min; m/z (ESI⁺) 466 (MH⁺)

Synthesis 115 Methyl6-(5-cyanopyrazin-2-ylamino)-4-(methyl(1-methylpiperidin-4-yl)amino)nicotinate(Y-070)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A and 62-B.

¹H NMR (500 MHz, d₄-MeOD) δ 9.00 (1H, s), 8.62 (1H, s), 8.42 (1H, s),7.46 (1H, s), 3.90 (3H, s), 3.40-3.50 (1H, m), 3.00-3.05 (2H, m), 2.83(3H, s), 2.35 (3H, s), 2.10-2.20 (2H, m), 1.90-2.00 (2H, m) and1.85-1.90 (2H, m). LCMS (3B) Rt=1.58 min; m/z (ESI⁺) 382 (MH⁺).

Synthesis 116 Methyl6-(5-cyanopyrazin-2-ylamino)-4-(9-methyl-9-azabicyclo[3.3.1]-nonan-3-ylamino)nicotinate(Y-071)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A and 62-B.

¹H NMR (500 MHz, d₄-MeOD) δ 8.95 (1H, s), 8.65 (1H, s), 8.62 (1H, s),7.22 (1H, s), 4.05-4.15 (1H, m), 3.88 (3H, s), 3.35-3.40 (2H, m), 2.75(3H, s), 2.60-2.70 (2H, m), 2.05-2.20 (2H+1H, m), 1.45-1.55 (2H+1H, m)and 1.35-1.45 (2H, m). LCMS (3B) RT=1.85 min; m/z (ESI⁺) 408 (MH⁺).

Synthesis 117-A((1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)methanamine

To a solution of(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-carbonitrile (J. Org.Chem., 1977, 3114) (83 mg, 0.55 mmol) in NH₃/MeOH (0.5%) (10 mL) wasadded Raney Ni (ca. 50 mg). The reaction mixture was hydrogenated atatmospheric pressure for 16 hours. After filtration, the solvents wereevaporated and the oil was purified by ion exchange on SCX-II acidicresin (2 g) eluting with methanol, then 2M ammonia-methanol. The basicfractions were combined and the solvent was removed in vacuo to give((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)methanamine ascolourless oil (32 mg, 38%).

¹H NMR (500 MHz, d₄-MeOD) δ 2.45-2.55 (1H, m), 2.35-2.45 (1H, m), 2.28(3H, s), 2.05-2.15 (2H, m), 1.70-1.80 (1H, m), 1.55-1.70 (4H, m) and1.30-1.40 (2H, m).

Synthesis 117-B Methyl6-(5-cyanopyrazin-2-ylamino)-4-(((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)methylamino)nicotinate(Y-072)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A and 62-B.

¹H NMR (500 MHz, d₄-MeOD) δ 8.88 (1H, s), 8.67 (1H, s), 8.64 (1H, s),7.34 (1H, s), 3.90-4.00 (2H, m), 3.88 (3H, s), 3.55-3.60 (2H, m), 2.80(3H, s), 2.25-2.45 (3H, m), 1.95-2.05 (4H, m), and 1.75-1.85 (2H, m).LCMS (3B) Rt=1.64 min; m/z (ESI⁺) 408 (MH⁺).

Synthesis 118 Methyl6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-2-ylmethylamino)-nicotinate(Y-073)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A, 62-B and 62-C.

¹H NMR (500 MHz, d₄-MeOD) δ 8.93 (1H, s), 8.60 (1H, s), 8.57 (1H, s),7.16 (1H, s), 3.87 (3H, s), 3.25-3.30 (2H, m), 3.05-3.10 (1H, m),2.85-2.95 (1H, m), 2.60-2.70 (1H, m), 1.75-1.90 (2H, m), 1.65-1.70 (1H,m), 1.40-1.55 (2H, m) and 1.20-1.30 (1H, m). LCMS (3B) Rt=1.76 min; m/z(ESI⁺) 368 (MH⁺).

Synthesis 119 (1R,5R)-tert-Butyl3-(2-(5-cyanopyrazin-2-ylamino)-5-(methoxycarbonyl)pyridin-4-ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate(Y-074)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A and 62-B.

¹H NMR (500 MHz, CDCl3) δ 8.68 (s, 2H), 8.49 (s, 1H), 8.09 (d, 1H, J=7.5Hz), 7.41 (s, 1H), 4.37 (br s, 2H), 4.06-3.95 (m, 1H), 3.89 (s, 3H),2.18-2.07 (m, 4H), 1.81-1.53 (m, 4H (under water peak)), 1.51 (s, 9H).LCMS (3B) Rt=4.78 min; m/z (ESI⁺) 480 (MH⁺).

Synthesis 120 Methyl4-((1R,5R)-8-azabicyclo[3.2.1]octan-3-ylamino)-6-(5-cyanopyrazin-2-ylamino)nicotinate(Y-075)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A, 62-B and 62-C.

¹H NMR (500 MHz, DMSO) δ 9.06 (s, 1H), 8.76 (s, 1H), 8.59 (s, 1H), 7.77(d, 1H, J=7.5), 7.32 (s, 1H), 3.80 (s, 3H), 3.78-3.70 (m, 1H), 3.51-3.46(m, 2H), 2.01-1.94 (m, 2H), 1.81-1.72 (m, 4H), 1.44-1.37 (m, 2H). LCMS(3B) Rt=1.81 min; m/z (ESI⁺) 380 (MH⁺).

Synthesis 121 Methyl4-(azepan-4-ylamino)-6-(5-cyanopyrazin-2-ylamino)nicotinate (Y-076)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A, 62-B and 62-C.

¹H NMR (500 MHz, CDCl₃) δ 8.68 (d, 1H, J=1.0 Hz), 8.70 (s, 1H), 8.51 (d,1H, J=1.0 Hz), 8.34 (d, 1H, J=7.5 Hz), 7.26 (s, 1H), 3.89 (s, 3H),3.86-3.78 (m, 1H), 3.11-2.92 (m, 5H), 2.20-2.15 (m, 1H), 2.10-2.01 (m,1H), 1.90-1.70 (m, 5H). LCMS (3B) Rt=1.76 min. m/z (ESI⁺) 368 (MH⁺).

Synthesis 122 Methyl6-(5-cyanopyrazin-2-ylamino)-4-(1-propylpiperidin-4-ylamino)nicotinate(Y-077)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A and 62-B.

¹H NMR (500 MHz, CDCl₃) δ 8.80 (1H, s), 8.70 (1H, s), 8.52 (1H, s), 8.30(1H, s, broad, NH), 7.20 (1H, s), 3.91 (3H, s), 3.50-3.60 (1H, m),2.85-3.00 (2H, m), 2.30-2.50 (4H, m), 2.10-2.25 (2H, m), 1.70-1.90 (2H,m), 1.50-1.70 (2H, m) and 0.88-1.00 (3H, t, J=6.5 Hz). LCMS (3B) R_(t)1.79 min; m/z (ESI⁺) 396 (MH⁺).

Synthesis 123 Methyl6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylamino)nicotinate (Y-078)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A, 62-B and 62-C.

¹H NMR (500 MHz, MeOD) δ 8.94 (s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 7.23(s, 1H), 3.87 (s, 3H), 3.68-3.59 (m, 1H), 3.16-3.09 (m, 2H), 2.86-2.76(m, 2H), 2.15-2.08 (m, 2H), 1.58-1.50 (m, 2H). LCMS (3B) Rt=1.46 min;m/z (ESI⁺) 354 (MH⁺).

Synthesis 124 Methyl6-(5-cyanopyrazin-2-ylamino)-4-(8-propyl-8-azabicyclo[3.2.1]octan-3-ylamino)nicotinate(Y-079)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A and 62-B.

¹H NMR (500 MHz, d₄-MeOD) δ 8.93 (1H, s), 8.65 (1H, s), 8.59 (1H, s),7.07 (1H, s), 3.90 (3H, s), 3.45-3.50 (1H, m), 2.50-2.60 (2H, m),2.30-2.40 (2H, m), 2.00-2.20 (4H, m), 1.85-1.95 (2H, m), 1.70-1.80 (1H,m), 1.55-1.70 (2H, m), 1.25-1.40 (1H, m) and 0.95-1.05 (3H, t, J=6.5Hz). LCMS (3B) Rt 1.96 min; m/z (ESI⁺) 422 (MH⁺).

Synthesis 125 Methyl6-(5-cyanopyrazin-2-ylamino)-4-(8-(pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-ylamino)nicotinate(Y-080)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A and 62-B.

¹H NMR (500 MHz, d₄-MeOD) δ 8.92 (1H, s), 8.68 (1H, s), 8.60 (1H, s),8.50-8.60 (1H, m), 7.85-7.90 (1H, m), 7.65-7.70 (1H, m), 7.35-7.40 (1H,m), 7.15 (1H, s), 4.03 (2H, s), 3.90 (3H, s), 3.50-3.65 (2H, m),2.40-2.50 (1H, m), 2.30-2.40 (2H, m), 2.12-2.24 (2H, m), 1.90-2.10 (2H,m), 1.78-1.90 (1H, m), and 1.55-1.68 (1H, m). LCMS (3B) Rt 2.16 min; m/z(ESI⁺) 471 (MH⁺).

Synthesis 126 Methyl6-(5-cyanopyrazin-2-ylamino)-4-(morpholin-2-ylmethylamino)nicotinate(Y-081)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A, 62-B and 62-C.

¹H NMR (500 MHz, d₆-DMSO) δ 10.82 (1H, s, broad, NH), 9.00 (1H, s), 8.80(1H, s), 8.60 (1H, s), 8.16 (1H, s, broad, NH), 7.24 (1H, s), 3.81 (3H,s), 3.75-3.80 (1H, m), 3.60-3.65 (1H, m), 3.42-3.50 (1H, m), 3.20-3.30(1H, m), 3.10-3.20 (2H, m), 2.80-2.90 (1H, m), 2.60-2.70 (2H, m), and2.42-2.50 (1H, m). LCMS (4)1.16 min; m/z (ESI⁺) 370 (MH⁺).

Synthesis 127 (S)-Methyl6-(5-cyanopyrazin-2-ylamino)-4-(2-(morpholin-2-yl)ethylamino)nicotinate(Y-082)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A, 62-B and 62-C.

¹H NMR (500 MHz, d₄-MeOD) δ 8.90 (1H, s), 8.63 (1H, s), 8.60 (1H, s),7.25 (1H, s), 3.88-3.95 (1H, m), 3.87 (3H, s), 3.50-3.70 (2H, m),3.40-3.50 (2H, m), 2.85-2.95 (1H, m), 2.80-2.85 (2H, m), 2.55-2.65 (1H,m), and 1.70-1.85 (2H, m). LCMS (4) Rt 1.22 min; m/z (ESI⁺) 384 (MH⁺).

Synthesis 128 Methyl6-(5-Cyanopyrazin-2-ylamino)-4-((4-fluoropiperidin-4-yl)methylamino)nicotinate(Y-083)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 62, steps 62-A, 62-B and 62-C.

¹H NMR (500 MHz, d₄-MeOD) δ 8.92 (1H, s), 8.66 (1H, s), 8.64 (1H, s),7.31 (1H, s), 3.90 (3H, s), 3.50-3.60 (2H, d, J=21 Hz), 2.95-3.10 (4H,m), 1.97-2.05 (2H, m), and 1.75-1.90 (2H, m). LCMS (4) R_(t) 1.28 min;m/z (ESI⁺) 386 (MH⁺).

Synthesis 1296-(5-Cyanopyrazin-2-ylamino)-N-(2-methoxyethyl)-4-(piperidin-4-ylmethylamino)nicotinamide

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR (CDCl₃, 500 MHz) 8.97 (d, 1H, J=1.3 Hz), 8.61 (d, 1H, J=1.3 Hz),8.34 (s, 1H), 7.14 (s, 1H), 3.59-3.57 (m, 2H), 3.55-3.53 (m, 2H), 3.41(s, 3H), 3.33 (dt, 2H J=3.3, 1.6 Hz), 3.20-3.17 (m, 3H), 2.73 (dd, 2HJ=12.5, 10.1 Hz), 1.90-1.88 (m, 3H), 1.37-1.35 (m, 3H); LC-MS (3B) Rt1.48 min; m/z (ESI⁺) 411 [MH⁺].

Synthesis 1306-(5-Cyanopyrazin-2-ylamino)-N-ethyl-4-(1-methylpiperidin-4-ylamino)nicotinamide(Y-085)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A.

LCMS (3B) Rt 1.11 min; m/z (ESI⁺) 381 (MH⁺).

Synthesis 1316-(5-Cyanopyrazin-2-ylamino)-N-isopropyl-4-(piperidin-4-ylmethylamino)nicotinamide(Y-086)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR (500 MHz, d4-MeOD) δ 8.96 (1H, s), 8.58 (1H, s), 8.30 (1H, s),7.07 (1H, s), 4.10-4.20 (1H, m), 3.10-3.20 (4H, m), 2.60-2.70 (2H, m),1.80-1.90 (3H, m), 1.25-1.35 (2H, m) and 1.20 (6H, d, J=6.8 Hz). LCMS(3B) R_(t) 1.68 min; m/z (ESI⁺) 395 (MH⁺).

Synthesis 1325-(4-(Piperidin-4-ylmethylamino)-5-(pyrrolidine-1-carbonyl)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-087)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR (MeOD-d₄, 500 MHz,) 8.95 (s, 1H), 8.60 (s, 1H), 8.36 (s, 1H),7.13 (s, 1H), 3.71 (t, 1H, J=5.8 Hz), 3.48 (t, 1H, J=5.8 Hz), 3.32-3.31(m, 1H), 3.20-3.14 (m, 3H), 2.73 (t, 2H, J=11.4 Hz), 2.00-1.89 (m, 3H),1.39-1.33 (m, 3H); LCMS (3B) Rt 0.93 min; m/z (ESI⁺) 407 [MH⁺].

Synthesis 1336-(5-Cyanopyrazin-2-ylamino)-N-(2-hydroxyethyl)-4-(piperidin-4-ylmethylamino)nicotinamide(Y-088)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR (MeOD-d₄, 500 MHz) 8.97 (s, 1H), 8.58 (s, 1H), 8.05 (s, 1H), 7.13(s, 1H), 3.65-3.55 (m, 4H), 3.26-3.23 (m, 2H), 3.17-3.14 (m, 2H), 2.79(t, 2H, J=11.4 Hz), 2.04-1.89 (m, 7H); LCMS (3B) Rt 1.08 min; m/z (ESI⁺)397 [MH⁺].

Synthesis 1345-(5-(Morpholine-4-carbonyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-089)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR (MeOD-d₄, 500 MHz) 8.97 (d, 1H, J=1.2 Hz), 8.58 (d, 1H, J=1.2Hz), 7.90 (s, 1H), 7.15 (s, 1H), 3.84-3.58 (m, 8H), 3.23-3.10 (m, 4H),2.68 (dd, 2H, J=10.1, 12.5 Hz), 1.87-1.85 (m, 3H), 1.32-1.30 (m, 3H);LCMS (3B) Rt 0.66 min; m/z (ESI⁺) 423 [MH⁺].

Synthesis 1356-(5-Cyanopyrazin-2-ylamino)-N,N-dimethyl-4-(piperidin-4-ylmethyl-amino)nicotinamide(Y-090)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR (500 MHz, d₄-MeOD) δ 8.97 (1H, s), 8.58 (1H, s), 7.90 (1H, s),7.14 (1H, s), 3.12 (6H, s), 3.00-3.20 (4H, m), 2.55-2.75 (2H, m),1.75-1.95 (3H, m) and 1.20-1.40 (2H, m). LCMS (3B) Rt 0.67 min; m/z(ESI⁺) 381 (MH⁺).

Synthesis 1366-(5-Cyanopyrazin-2-ylamino)-N-(2-methoxyethyl)-N-methyl-4-(piperidin-4-ylmethylamino)nicotinamide(Y-091)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR (CDCl₃, 500 MHz) 8.84 (d, 1H, J=1.3 Hz), 8.50 (d, 1H, J=1.3 Hz),7.93 (s, 1H), 7.18 (s, 1H), 3.69-3.68 (m, 2H), 3.61-3.60 (m, 2H), 3.36(3H, s), 3.11-3.09 (m, 7H), 3.10 (t, 2H, J=6.0 Hz), 2.60 (t, 2H, J=11.7Hz), 1.82-1.80 (m, 3H), 1.27-1.20 (m, 2H); LCMS (3B) Rt 0.87 min; m/z(ESI⁺) 425 [MH⁺].

Synthesis 1376-(5-Cyanopyrazin-2-ylamino)-N-(4-fluorophenyl)-4-(piperidin-4-ylmethylamino)nicotinamide(Y-092)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR (MeOD-d₄, 500 MHz) δ 8.99 (d, 1H, J=1.4 Hz), 8.60 (d, 1H, J=1.4Hz), 8.49 (s, 1H), 7.95 (s, 1H), 7.63-7.60 (m, 2H), 7.14 (s, 1H),7.10-7.07 (m, 2H), 3.16 (d, 2H, J=6.2 Hz), 3.12 (d, 2H, J=12.2 Hz),2.68-2.63 (m, 2H), 1.89-1.84 (m, 2H), 1.36-1.29 (m, 3H). LCMS (3B)Rt=2.09 min; m/z (ESI⁺) 447 (MH⁺).

Synthesis 1386-(5-Cyanopyrazin-2-ylamino)-N-(2-fluorophenyl)-4-(piperidin-4-ylmethylamino)nicotinamide(Y-093)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR ((CD₃)₂SO-d₆, 500 MHz) δ 10.04 (br s, 1H), 9.08 (s, 1H), 8.80 (s,1H), 8.67 (s, 1H), 8.46 (br s, 1H), 7.93 (s, 1H), 7.51 (t, 1H, J=7.6Hz), 7.30-7.28 (m, 2H), 7.24-7.22 (m, 1H), 7.20 (s, 1H), 3.10-3.04 (m,2H), 2.97 (d, 2H, J=12 Hz), 2.47-2.45 (m, 2H), 1.71-1.65 (m, 3H),1.32-1.23 (m, 1H), 1.21-1.11 (m, 2H). LCMS (3B) Rt=1.97 min; m/z (ESI⁺)447 (MH⁺).

Synthesis 1396-(5-Cyanopyrazin-2-ylamino)-N-(3-fluorophenyl)-4-(piperidin-4-ylmethylamino)nicotinamide(Y-094)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR ((CD₃)₂SO-d₆, 500 MHz) δ 10.31 (s, 1H), 9.11 (s, 1H), 8.80 (s,1H), 8.61 (s, 1H), 8.26 (br s, 1H), 7.93 (s, 1H), 7.66 (d, 1H, J=11.8Hz), 7.51-7.46 (m, 1H), 7.41-7.36 (m, 1H), 7.20 (s, 1H), 6.95-6.92 (m,1H), 3.12-3.08 (m, 2H), 3.02 (d, 2H, J=12 Hz), 2.55-2.53 (m, 2H),1.72-1.69 (m, 3H), 1.24-1.16 (m, 3H). LCMS (3B) Rt=2.16 min; m/z (ESI⁺)447 (MH⁺).

Synthesis 1406-(5-Cyanopyrazin-2-ylamino)-N-(4-methoxyphenyl)-4-(piperidin-4-ylmethylamino)nicotinamide(Y-095)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR ((CD₃)₂SO-d₆, 500 MHz) δ 10.04 (s, 1H), 9.11 (s, 1H), 8.79 (s,1H), 8.59 (s, 1H), 8.37 (br s, 1H), 7.93 (s, 1H), 7.58 (d, 2H, J=8.8Hz), 7.16 (s, 1H), 6.92 (d, 2H, J=8.8 Hz), 3.75 (s, 3H), 3.08 (m, 2H),3.00 (d, 2H, J=11.8 Hz), 2.50-2.49 (m, 2H), 1.70-1.67 (m, 3H), 1.24-1.15(m, 3H). LCMS (4) Rt=1.48 min; m/z (ESI⁺) 459 (MH⁺).

Synthesis 1416-(5-Cyanopyrazin-2-ylamino)-N-(3-methoxyphenyl)-4-(piperidin-4-ylmethylamino)nicotinamide(Y-096)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR ((CD₃)₂SO-d₆, 500 MHz) δ 10.11 (s, 1H), 9.12 (s, 1H), 8.79 (d,1H, J=1.2 Hz), 8.59 (s, 1H), 8.29 (t, 1H, J=5.6 Hz), 7.93 (s, 1H), 7.35(s, 1H), 7.31 (d, 1H, J=8 Hz), 7.24 (t, 1H, J=8.1 Hz), 7.17 (s, 1H),6.70-6.68 (m, 1H), 3.76 (s, 3H), 3.08 (t, 2H, J=5.7 Hz), 2.97 (d, 2H,J=12 Hz), 2.46 (t, 2H, J=12.2 Hz), 1.72-1.66 (m, 3H), 1.29-1.24 (m, 1H),1.18-1.10 (m, 2H). LCMS (4) Rt=1.50 min; m/z (ESI⁺) 459 (MH⁺).

Synthesis 1426-(5-Cyanopyrazin-2-ylamino)-N-(2-methoxyphenyl)-4-(piperidin-4-ylmethylamino)nicotinamide(Y-097)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR ((CD₃)₂SO-d₆, 500 MHz) δ 9.47 (s, 1H), 9.11 (s, 1H), 8.80 (s,1H), 8.63 (s, 1H), 8.44 (t, 1H, J=5.4 Hz), 7.93 (s, 1H), 7.58 (d, 1H,J=7.7 Hz), 7.21 (t, 1H, J=7.8 Hz), 7.16 (s, 1H), 7.10 (d, 1H, J=8.2 Hz),6.96 (t, 1H, J=7.6 Hz), 3.83 (s, 3H), 3.07 (t, 2H, J=5.5 Hz), 2.99 (d,2H, J=12 Hz), 2.47-2.45 (m, 2H), 1.72-1.66 (m, 3H), 1.26-1.22 (m, 1H),1.19-1.13 (m, 2H). LCMS (4) Rt=1.45 min; m/z (ESI⁺) 459 (MH⁺).

Synthesis 1436-(5-Cyanopyrazin-2-ylamino)-N-(4-(2-morpholinoethoxy)phenyl)-4-(piperidin-4-ylmethylamino)nicotinamide(Y-098)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR ((CD₃)₂SO-d₆, 500 MHz) δ 10.05 (s, 1H), 9.10 (s, 1H), 8.79 (d,1H, J=1.2 Hz), 8.57 (s, 1H), 8.35 (t, 1H, J=5.5 Hz), 7.92 (s, 1H), 7.56(d, 2H, J=9 Hz), 7.15 (s, 1H), 6.92 (d, 2H, J=9 Hz), 4.06 (t, 2H, J=5.8Hz), 3.59-3.57 (m, 4H), 3.05 (t, 2H, J=5.8 Hz), 2.96 (d, 2H, J=11.7 Hz),2.67 (t, 2H, J=5.7 Hz), 2.47-2.43 (m, 6H), 1.70-1.64 (m, 3H), 1.27-1.23(m, 1H), 1.16-1.10 (m, 2H). LCMS (4) Rt=1.08 min; m/z (ESI⁺) 558 (MH⁺).

Synthesis 1446-(5-Cyanopyrazin-2-ylamino)-N-(3-morpholinophenyl)-4-(piperidin-4-ylmethylamino)nicotinamide(Y-099)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR ((CD₃)₂SO-d₆, 500 MHz) δ 10.02 (s, 1H), 9.10 (s, 1H), 8.79 (d,1H, J=1.3 Hz), 8.56 (s, 1H), 8.29 (t, 1H, J=5.6 Hz), 7.92 (s, 1H), 7.27(s, 1H), 7.22-7.16 (m, 3H), 6.70 (d, 1H, J=7.8 Hz), 3.75-3.73 (m, 4H),3.09-3.05 (m, 6H), 2.95 (d, 2H, J=12 Hz), 2.45 (t, 2H, J=11.2 Hz),1.72-1.64 (m, 3H), 1.26-1.22 (m, 1H), 1.16-1.09 (m, 2H). LCMS (4)Rt=1.48 min; m/z (ESI⁺) 514 (MH⁺).

Synthesis 1456-(5-Cyanopyrazin-2-ylamino)-N-(4-morpholinophenyl)-4-(piperidin-4-ylmethylamino)nicotinamide(Y-100)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR (500 MHz, d₄-MeOD) δ 9.00 (1H, s), 8.60 (1H, s), 8.46 (1H, s),7.50 (2H, d, J=8.5 Hz), 7.10 (1H, s), 7.00 (2H, d, J=8.5 Hz), 3.80-3.90(4H, m), 3.05-3.20 (8H, m), 2.60-2.75 (2H, m), 1.80-1.95 (1H+2H, m), and1.25-1.45 (2H, m). LCMS (4) Rt=2.11 min; m/z (ESI⁺) 514 [MH⁺].

Synthesis 1466-(5-Cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)nicotinamide(Y-101)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR (MeOD-d₄, 500 MHz) δ 8.97 (s, 1H), 8.60 (s, 1H), 8.41 (s, 1H),7.12 (s, 1H), 3.14 (d, 2H, J=6 Hz), 3.09 (d, 2H, J=11.8 Hz), 2.62 (t,2H, J=11.6 Hz), 1.83 (d, 2H, J=10.8 Hz), 1.30-1.28 (m, 3H). LCMS (4)Rt=0.98 min; m/z (ESI⁺) 353 (MH⁺).

Synthesis 1476-(5-Cyanopyrazin-2-ylamino)-4-(morpholin-2-ylmethylamino)-N-phenylnicotinamide(Y-102)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A and 75-B.

¹H NMR (500 MHz, d₄-MeOD) δ 9.00 (1H, s), 8.65 (1H, s), 8.57 (1H, s),7.60-7.65 (2H, dd, J=1.5 and 8.3 Hz), 7.35-7.40 (2H, dd, J=7.8 and 8.3Hz), 7.26 (1H, s), 7.15-7.20 (1H, m), 4.10-4.20 (1H, m), 4.00-4.10 (1H,m), 3.84-3.94 (1H, m), 3.68-3.77 (1H, m), 3.40-3.50 (2H, m), 3.26-3.30(1H, m), 3.20-3.26 (1H, m), and 3.05-3.15 (1H, m). LCMS (4) Rt=1.81 min;m/z (ESI⁺) 431.1 [MH⁺].

Synthesis 1486-(5-Cyanopyrazin-2-ylamino)-4-(1-methylpiperidin-4-ylamino)-N-phenylnicotinamide(Y-103)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 75, steps 75-A.

¹H NMR ((CD₃)₂SO-d₆, 500 MHz) δ 10.67 (s, 1H), 10.13 (s, 1H), 9.11 (d,1H, J=1.2 Hz), 8.79 (d, 1H, J=1.4 Hz), 8.62 (s, 1H), 8.22 (d, 1H, J=7.1Hz), 7.67 (dd, 2H, J=8.4, 1.0 Hz), 7.34 (t, 2H, J=8.0 Hz), 7.20 (s, 1H),7.10 (t, 1H, J=8.0 Hz), 2.71 (d, 2H, J=10.8 Hz), 2.22 (s, 3H), 2.19-2.15(m, 2H), 1.98 (d, 2H, J=9.8 Hz), 1.52-1.50 (m, 2H). LCMS (4) Rt=1.50min; m/z (ESI⁺) 429 (MH⁺).

Synthesis 1496-(5-Cyanopyrazin-2-ylamino)-4-(1-methylpiperidin-4-ylamino)nicotinicacid (Y-104)

Methyl6-(5-cyanopyrazin-2-ylamino)-4-(1-methylpiperidin-4-ylamino)nicotinate(Synthesis 66) (50 mg, 0.136 mmol) and lithium iodide (36 mg, 2 eq.) indry pyridine (1.4 mL) were heated at 150° C. in a sealed Biotagemicrowave vial for 2.5 hr. The volatiles were removed in vacuo and thecrude mixture was partitioned between EtOAc and 1M aqueous NaHCO₃. Theaqueous layer was retained, washed with fresh EtOAc and then carefullyneutralised with 1M HCl. The volatiles were then removed and a portionof the residue was purified by HPLC to give the title compound as ayellow powder (5 mg,10%).

¹H NMR (500 MHz, DMSO) δ 9.03 (s, 1H), 8.88 (br s, 1H), 8.75 (s, 1H),8.54 (s, 1H), 8.18 (s, 1H), 7.11 (s, 1H), 3.45-3.39 (m, 1H), 2.96-2.87(m, 2H), 2.48-2.39 (m, 2H), 2.39 (s, 3H), 2.08-2.01 (m, 2H), 1.61-1.52(m, 2H). LCMS (3B) Rt=1.09 min; m/z (ESI⁺) 354 (MH⁺).

Synthesis 150 methyl4-(1-methylpiperidin-4-ylamino)-6-(5-methylpyrazin-2-ylamino)nicotinate(Y-105)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 81.

¹H NMR (500 MHz, CDCl₃) δ 8.68 (s, 1H), 8.52 (d, 1H, J=1.0 Hz), 8.15 (d,1H, J=7.0 Hz), 8.07 (s, 1H), 7.23 (s, 1H), 3.86 (s, 3H), 3.64 (s, 1H),3.53 (br s, 1H), 2.87-2.80 (m, 2H), 2.49 (s, 3H), 2.39 (s, 3H),2.41-2.34 (m, 2H), 2.18-2.11 (m, 2H),1.83-1.71 (m, 2H). LCMS (3B)Rt=1.56 min; m/z (ESI⁺) 357 (MH⁺).

Synthesis 151 Methyl6-(5-methoxypyrazin-2-ylamino)-4-(morpholin-2-ylmethylamino)nicotinate(Y-106)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 82, steps 82-A and 82-B, and Synthesis 75, step75-B.

¹H NMR (500 MHz, d₄-MeOD) δ 8.58 (1H, s), 8.46 (1H, s), 7.96 (1H, s),6.77 (1H, s), 3.98-4.02 (1H, m), 3.97 (3H, s), 3.87 (3H, s), 3.80-3.85(1H, m), 3.70-3.75 (1H, m), 3.35-3.40 (1H, m), 3.25-3.32 (1H, m),3.02-3.12 (1H, m), 2.88-2.95 (2H, m) and 2.70-2.80 (1H, m). LCMS (4)Rt=1.29 min; m/z (ESI⁺) 375 [MH⁺].

Synthesis 152-A (E)-tert-Butyl4-((5-((1-aminoethylideneaminooxy)carbonyl)-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

DIPEA (96 μL, 0.55 mmol) was added to a solution of4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)nicotinicacid (Synthesis 75-A) (50 mg, 0.11 mmol), HATU (54 mg, 0.14 mmol) in DMF(6 mL) under argon. The reaction mixture was stirred for 15 min at r.t.and (E)-N′-hydroxyacetimidamide (25 mg, 0.34 mmol) in DMF (0.5 mL) wasadded. The resulting solution was stirred at r.t. for 12 hr. AqueousNaCl solution (15 mL) was added and the resulting precipitate wascollected. The solid was washed with water and n-hexane to give a yellowpowder (43 mg, 77%).

¹H NMR (500 MHz, d₆-DMSO) δ 10.70 (1H, s, broad, NH), 9.10 (1H, s), 8.86(1H, s), 8.78 (1H, s), 8.20 (1H, s, broad, NH), 7.18 (1H, s), 6.50 (2H,s, broad, NH₂), 3.91-4.00 (2H, m), 3.05-3.15 (2H, m), 2.60-2.70 (2H, m),1.80 (3H, s), 1.60-1.70 (2H, m), 1.40 (9H, s) and 1.00-1.30 (2H, m).LCMS Rt=4.02 min; m/z (ESI⁺) 510 [MH⁺].

Synthesis 152-B tert-Butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

A solution of (E)-tert-Butyl4-((5-((1-aminoethylideneaminooxy)carbonyl)-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(40 mg, 0.078 mmol) in pyridine (3 mL) was heated at 120° C. for 8 hrusing microwave irradiation. After evaporation of the solvent, the crudeproduct was purified by column chromatography (Biotage), eluting withEtOAc/n-hexane (1/1), to give the title compound as a yellow solid (9mg, 23%).

¹H NMR (500 MHz, CDCl₃) δ 8.79 (1H, s), 8.77 (1H, s), 8.53 (1H, s), 8.30(1H, s, broad, NH), 7.32 (1H, s), 4.15-4.25 (2H, m), 3.25-3.30 (2H, m),2.70-2.80 (2H, m), 2.48 (3H, s), 1.90-2.00 (1H, m), 1.80-1.85 (2H, m),1.48 (9H, s) and 1.20-1.35 (2H, m). LCMS Rt=5.32 min; m/z (ESI⁺) 492[MH⁺].

Synthesis 152-C5-(5-(3-Methyl-1,2,4-oxadiazol-5-yl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-107)

To a solution of tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(9 mg, 0.018 mmol) in dichloromethane (3 mL) was added trifluoroaceticacid (0.15 mL) at r.t. After 3 hr, the solution was evaporated todryness and purified by ion exchange on SCX-II acidic resin (500 mg)eluting with methanol, then 2M ammonia-methanol. The basic fractionswere combined and the solvent was removed in vacuo to give the titlecompound as a yellow solid (4 mg, 56%).

¹H NMR (500 MHz, d₆-DMSO) δ 9.03 (1H, s), 8.82 (1H, s), 8.71 (1H, s),8.07 (1H, s, broad, NH), 7.34 (1H, s), 3.15-3.25 (4H, m), 2.90-3.00 (2H,m), 2.45 (3H, s), 1.60-1.80 (1H+2H, m), and 1.10-1.25 (2H, m). LCMSRt=2.18 min; m/z (ESI⁺) 392 [MH⁺].

Synthesis 153-A N-(4-Chloropyridin-2-yl)pivalamide

Trimethylacetyl chloride (4.22 g, 35.0 mmol) was added dropwise to asolution of 2-amino-4-chloropyridine (3.00 g, 23.3 mmol) in pyridine (11mL) at 0° C. The resulting solution was stirred for 12 h at r.t. Water(20 mL) was added and the aqueous phase was extracted with ethyl acetate(3×10 mL). The combined organic extracts were dried (MgSO₄). The solventwas removed in vacuo and the crude mixture was purified by flashchromatography on silica, eluting with ethyl acetate and hexane (2/8),to give the title compound as a colourless solid (4.9 g, 99%).

¹H NMR (CDCl₃, 500 MHz) δ 8.37 (d, 1H, J=1.9 Hz), 8.17 (s, 1H), 8.15 (d,1H, J=5.3 Hz), 7.05 (1H, dd, J=1.9, 5.3 Hz), 1.33 (9H, s). LCMS (3B)Rt=2.45 min; m/z (ESI⁺) 213 [MH⁺].

Synthesis 153-B N-(4,5-Dichloropyridin-2-yl)pivalamide

NCS (3.14 g. 23.5 mmol) was added to a solution ofN-(4-chloropyridin-2-yl)pivalamide (1.00 g, 4.7 mmol) in dryacetonitrile (10 mL). The resulting suspension was heated for 3 h andthen cooled to r.t. The solvent was removed in vacuo and the crudemixture was diluted with ethyl acetate (50 mL). The organic phase waswashed with aqueous NaOH (10%, 2×20 mL), water (20 mL) and dried(MgSO₄). The solvent was removed in vacuo and the crude mixture waspurified by flash chromatography on silica, eluting with ethyl acetateand hexane (1/9), to give the title compound as a colourless solid (0.87g, 75%).

¹H NMR (CDCl₃, 500 MHz) δ 8.46 (s, 1 H), 8.24 (s, 1 H), 1.31 (9H, s).LCMS (3B) Rt=2.72 min; m/z (ESI⁺) 247 [MH⁺].

Synthesis 153-CN-(5-Chloro-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide

A solution of N-(4,5-dichloropyridin-2-yl)pivalamide (0.400 g, 1.62mmol), N-methyl-4-aminopiperidine (0.185 g, 1.62 mmol) in NMP (3 mL) washeated at 220° C. under microwave irradiation for 3 h. The crudereaction mixture was purified by ion exchange on SCX-II acidic resin (2g) eluting with methanol/dichloromethane (1/1), then 2Mammonia-methanol. The basic fractions were combined and the solvent wasremoved in vacuo. The crude mixture was purified by flash chromatographyon silica, eluting with methanol and dichloromethane (1/9), to give thetitle compound as a colourless solid (0.384 g, 73%).

¹H NMR (Acetone-d₆, 500 MHz) δ 8.51 (s, 1H), 7.88 (s, 1H), 7.70 (s, 1H),5.46 (d, 1H, J=7.9 Hz), 3.56-3.49 (1H, m), 3.04-3.01 (m, 2H), 2.50-2.45(m, 2H), 2.42 (s, 3H), 2.09-2.06 (m, 2H), 1.89-1.86 (m, 2H). LCMS (3B)Rt=1.00 min; m/z (ESI⁺) 325 [MH⁺].

Synthesis 153-D 5-Chloro-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine

A solution ofN-(5-chloro-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide(0.609 g, 1.87 mmol) in 6M HCl (5 mL) was heated under microwaveirradiation at 105° C. for 50 min. The solution was basified with Na₂CO₃and extracted with ethyl acetate (3×20 mL). The crude mixture waspurified by flash chromatography on silica, eluting with methanol anddichloromethane (1/9), to give the title compound as a colourless solid(0.300 g, 66%).

¹H NMR (MeOD-d₄, 500 MHz) δ 7.58 (s, 1H), 5.87 (s, 1H), 3.44-3.28 (m,1H), 2.86 (d, 2H, J=11.8 Hz), 2.30 (s, 3H), 2.20 (t, 2H, J=11.0 Hz),2.01 (d, 2H, J=14.2 Hz), 1.60-1.62 (m, 2H). LCMS (3B) Rt=0.52 min; m/z(ESI⁺) 241 [MH⁺].

Synthesis 153-E5-(5-Chloro-4-(1-methylpiperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-108)

A solution of 5-chloro-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine(0.080 g, 0.33 mmol), 2-bromo-cyanopyrazine (0.040 g, 0.22 mmol), BINAP(0.005 g, 0.02 mmol), sodium tert-butoxide (0.030 g, 0.31 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (0.009 g, 0.01mmol) in dioxane (1.6 mL) was stirred at r.t. under nitrogen for 10 minbefore being heated under microwave irradiation for 30 min at 90° C. Thecrude reaction mixture was purified by ion exchange on SCX-II acidicresin (1 g) eluting with methanol/dichloromethane (1/1), then 2Mammonia-methanol. The basic fractions were combined and the solvent wasremoved in vacuo. The crude mixture was purified by preparative thinlayer chromatography eluting with methanol/dichloromethane (1/9) to givethe title compound as a yellow solid (0.023 g, 30%).

¹H NMR (MeOD-d₄, 500 MHz) δ 8.94 (s, 1H), 8.57 (s, 1H), 7.96 (s, 1H),7.18 (s, 1H), 3.53-3.47 (m, 1H), 3.00-2.98 (m, 2H), 2.40 (s, 3H),2.38-2.35 (m, 2H), 2.13-2.09 (m, 2H), 1.75-1.67 (m, 2H). LC-MS (3B)Rt=0.67 min; m/z (ESI⁺) 344 [MH⁺].

Synthesis 1545-(5-Chloro-4-(methyl(1-methylpiperidin-4-y0amino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-109)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 153, steps 153-A, 153-B, 153-C, 153-D and 153-E.

¹H NMR (500 MHz, MeOD) δ 8.94 (d, 1H, J=1.0 Hz). 8.59 (d, 1H, J=1.0 Hz),8.12 (s, 1H), 7.55 (s, 1H), 3.94-3.84 (m, 1H), 3.48-3.41 (m, 2H),2.98-2.89 (m, 2H), 2.87 (s, 3H), 2.76 (s, 3H), 2.20-2.09 (m, 2H),2.06-1.97 (m, 2H). LCMS (4) Rt=1.43 min; m/z (ESI⁺) 358 (MH⁺).

Synthesis 155-A N-(5-Bromo-4-chloropyridin-2-yl)pivalamide

NBS (8.37 g. 47.0 mmol) was added to a solution ofN-(4-chloropyridin-2-yl)pivalamide (2.00 g, 9.40 mmol) in dryacetonitrile (20 mL). The resulting suspension was heated for 3 hr andthen cooled to r.t. The solvent was removed in vacuo and the crudemixture was diluted with ethyl acetate (100 mL). The organic phase waswashed with aqueous NaOH (10%, 2×40 mL), water (40 mL) and dried(MgSO₄). The solvent was removed in vacuo and the crude mixture waspurified by flash chromatography on silica, eluting with ethyl acetateand hexane (1/9), to give the title compound as a colourless solid (1.82g, 66%).

¹H NMR (CDCl₃, 500 MHz) δ 8.46 (s, 1H), 8.34 (s, 1H). LCMS (3B) Rt=2.73min; m/z (ESI⁺) 292 [MH⁺].

Synthesis 155-BN-(5-Bromo-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide

A solution of N-(5-bromo-4-chloropyridin-2-yl)pivalamide (0.547 g, 1.87mmol), 1-methylpiperidin-4-amine (0.600 g, 5.25 mmol) in NMP (3.3 mL)was heated under nicrowave irradiation for 3 hr at 220° C. The crudemixture was purified by flash chromatography on silica, eluting withmethanol and dichloromethane (1/9), to give the title compound as acolourless oil (0.684 g, 99%).

¹H NMR (CDCl₃, 500 MHz) δ 8.00 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H),3.57-3.42 (m, 1H), 3.42-3.35 (1H, m), 2.80-2.78 (m, 2H), 2.31 (s, 3H),2.24 (t, 2H, J=9.8 Hz), 2.09-2.05 (m, 2H), 1.64-1.58 (m, 2H). LCMS (3B)Rt=1.04 min; m/z (ESI⁺) 369 [MH⁺].

Synthesis 155-C 5-Bromo-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine

A solution ofN-(5-bromo-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide(0.526, 1.42 mmol) in 6M HCl (6 mL) was heated under microwaveirradiation at 105° C. for 50 min. The solution was basified with Na₂CO₃and extracted with ethyl acetate (3×20 mL). The crude mixture waspurified by flash chromatography on silica, eluting with methanol anddichloromethane (1/9), to give the title compound as a colourless solid(0.288 g, 70%).

¹H NMR (CDCl₃, 500 MHz) δ 7.86 (s, 1H), 5.70 (s, 1H), 4.58 (d, 1H, J=7.3Hz), 3.35-3.24 (m, 1H), 2.80-2.77 (m, 2H), 2.31 (s, 3H), 2.18 (t, 2H,J=10.4 Hz), 2.08-1.98 (m, 2H), 1.64-1.57 (m, 2H). LC-MS (3B) Rt=0.52min; m/z (ESI⁺) 284 [MH⁺].

Synthesis 155-D5-(5-Bomo-4-(1-methylpiperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-110)

A solution of 5-bromo-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine(0.020 g, 0.070 mmol), 2-bromo-cyanopyrazine (0.013 g, 0.070 mmol),BINAP (0.002 g, 0.005 mmol), sodium tert-butoxide (0.009 g, 0.098 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (0.003 g, 0.003mmol) in dioxane (0.5 mL was stirred at r.t. under nitrogen for 10 minbefore being heated for 6 h at 90° C. The crude reaction mixture waspurified by ion exchange on SCX-II acidic resin (1 g) eluting withmethanol/dichloromethane (1/1), then 2M ammonia-methanol. The basicfractions were combined and the solvent was removed in vacuo. The crudemixture was purified by preparative thin layer chromatography elutingwith methanol/dichloromethane (1/9) to give the title compound as ayellow solid (0.002 g, 7%).

¹H NMR (MeOD-d₄, 500 MHz) δ 8.87 (s, 1H), 8.60 (s, 1H), 8.12 (s, 1H),7.31 (s, 1H), 3.86-3.77 (m, 1H), 3.61-3.56 (m, 2H), 2.94 (s, 3H),2.37-2.31 (m, 2H), 2.03-1.91 (m, 2H), 1.30-1.28 (m, 2H). LCMS (4)Rt=1.06 min; m/z (ESI⁺) 387 [MH⁺].

Synthesis 156-A N4-(1-Methylpiperidin-4-yl)-5-phenylpyridine-2,4-diamine

A solution of theN-(5-chloro-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide(Synthesis 153-C) (0.187 g, 0.57 mmol), phenyl boronic acid (0.140 g,1.15 mmol), sodium carbonate (0.153 g, 1.43 mmol) and Bedford catalyst(0.003 g, 0.005 mmol) in a mixture of actonitrile/water (4/1, 3.1 mL)was heated under microwave irradiation for 30 min at 130° C. The crudereaction mixture was purified by ion exchange on SCX-II acidic resin (1g) eluting with methanol/dichloromethane (1/1), then 2Mammonia-methanol. The basic fractions were combined and the solvent wasremoved in vacuo. The crude mixture was used without furtherpurification. A solution of the protected amine in 6 M HCl (3 mL) washeated under microwave irradiation at 105° C. for 50 min. The solutionwas basified with Na₂CO₃ and extracted with ethyl acetate (3×10 mL). Thecrude mixture was purified by flash chromatography on silica, elutingwith methanol and dichloromethane (1/9), to give the title compound as acolourless solid (0.384 g, 73%).

¹H NMR (MeOD-d₄, 500 MHz) δ 7-50-7.47 (m, 2H), 7.41-7.40 (m, 1H), 7.38(s, 1H), 7.35-7.34 (m, 2H), 6.06 (s, 1H), 3.51-3.49 (m, 1H), 2.88-2.75(m, 2H), 2.38-2.27 (m, 5H), 2.05-1.96 (m, 2H), 1.53-1.49 (m, 2H). LCMS(3B) Rt=2.11 min; m/z (ESI⁺) 480 [MH⁺].

Synthesis 156-B5-(4-(1-Methylpiperidin-4-ylamino)-5-phenylpyridin-2-ylamino)pyrazine-2-carbonitrile(Y-111)

A solution of N4-(1-methylpiperidin-4-yl)-5-phenylpyridine-2,4-diamine(0.050 g, 0.17 mmol), 2-bromo-5-cyanopyrazine (0.022 g, 0.12 mmol),BINAP (0.003 g, 0.01 mmol), sodium tert-butoxide (0.016 g, 0.16 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (0.005 g, 0.01mmol) in toluene (0.7 mL) was stirred at r.t. under nitrogen for 10 minbefore being heated under microwave irradiation for 30 min at 90° C. Thecrude reaction mixture was purified by ion exchange on SCX-II acidicresin (0.5 g) eluting with methanol/dichloromethane (1/1), then 2Mammonia-methanol. The basic fractions were combined and the solvent wasremoved in vacuo. The crude mixture was purified by preparative thinlayer chromatography eluting with methanol/dichloromethane (1/9) to givethe desired compound as a yellow solid (0.008 g, 17%).

¹H NMR (500 MHz, MeOD-d₄) δ 8.73 (d, 1H, J=1.2 Hz), 8.63 (d, 1H, J=1.2Hz), 7.78 (s, 1H), 7.60-7.46 (m, 5H), 6.89 (s, 1H), 4.06-4.00 (m, 1H),3.62-3.59 (m, 2H), 3.36-3.30 (m, 2H), 2.91 (s, 3H), 2.31-2.28 (m, 2H),1.96-1.88 (m, 2H). LCMS (3B) Rt=1.61 min; m/z (ESI⁺) 386 [MH⁺].

Synthesis 1575-(4-(1-methylpiperidin-4-ylamino)-5-(thiophen-3-yl)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-112)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 156, steps 156-A and 156-B.

¹H NMR (500 MHz, MeOD) δ 8.91 (s, 1H), 8.57 (s, 1H), 7.88 (s, 1H), 7.62(dd, 1H, J=5.0, 3.0 Hz), 7.50 (dd, 1H, J=3.0, 1.5 Hz), 7.23 (dd, 1H,J=5.0, 1.5 Hz), 7.15 (s, 1H), 3.65-3.58 (m, 1H), 3.16-3.08 (m, 2H),2.75-2.66 (m, 2H), 2.58 (s, 3H), 2.22-2.15 (m, 2H), 1.71-1.61 (m, 2H).LCMS (3B) Rt=1.59 min; m/z (ESI⁺) 392 (MH⁺).

Synthesis 1585-(4-(methyl(1-methylpiperidin-4-yl)amino)-5-phenylpyridin-2-ylamino)pyrazine-2-carbonitrile(Y-113)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 156, steps 156-A and 156-B.

¹H NMR (500 MHz, MeOD) δ 9.01 (d, 1H, J=1.0 Hz), 8.61 (d, 1H, J=1.0 Hz),7.95 (s, 1H), 7.49 (s, 1H), 7.50-7.46 (m, 5H), 7.41-7.35 (m, 1H),3.46-3.37 (s, 1H), 3.29-3.20 (m, 2H), 2.73 (s, 3H), 2.61 (s, 3H),2.43-2.32 (m, 2H), 1.98-1.86 (m, 2H), 1.67-1.59 (m, 2H). LCMS (4)Rt=1.35 min; m/z (ESI⁺) 400 (MH⁺).

Synthesis 1595-(5-(4-methoxyphenyl)-4-(1-methylpiperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-114)

The title compound was prepared from the product of Synthesis 155-Dusing methods analogous to those described in Synthesis 156, steps 156-Aand 156-B.

¹H NMR (500 MHz, MeOD) δ 8.89 (s, 1H), 8.56 (s, 1H), 7.75 (s, 1H), 7.32(d, 2H, J=8.5 Hz), 7.06 (d, 2H, J=8.5 Hz), 7.11 (s, 1H), 3.86 (s, 3H),3.64-3.54 (m, 1H), 3.16-3.04 (m, 2H), 2.72-2.62 (m, 2H), 2.55 (s, 3H),2.19-2.11 (s, 2H), 1.69-1.56 (m, 2H). LCMS (4) Rt=1.36 min; m/z (ESI⁺)416 (MH⁺).

Synthesis 1605-(5-(3-(methoxymethyl)phenyl)-4-(1-methylpiperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-115)

The title compound was prepared from the product of Synthesis 155-Cusing methods analogous to those described in Synthesis 167, steps 167-Cand 167-D.

¹H NMR (CDCl₃, 500 MHz) δ 8.81 (s, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.83(s, 1H), 7.51-7.48 (m, 1H), 7.42-7.38 (m, 1H), 7.31-7.32 (m, 1H), 7.12(s, 1H), 4.53 (s, 2H), 3.58-3.45 (m, 2H), 2.83-2.81 (m, 2H), 2.38 (s,3H), 2.33-2.29 (m, 2H), 2.12-2.09 (m, 2H), 1.65-1.60 (m, 2H). LCMS (4)R_(t) 1.32 min; m/z (ESI⁺) 430 [MH³⁰].

Synthesis 1615-(5-(3-Methoxyphenyl)-4-(1-methylpiperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-116)

The title compound was prepared from the product of Synthesis 155-Cusing methods analogous to those described in Synthesis 167, steps 167-Cand 167-D.

¹H NMR (500 MHz, MeOD) δ 8.92 (s, 1H), 8.57 (s, 1H), 7.80 (s, 1H), 7.42(dd, 1H, J=8.0, 8.0 Hz), 7.14 (s, 1H), 7.02-6.93 (m, 3H), 3.85 (s, 3H),3.63-3.55 (m, 1H), 3.12-2.99 (m, 2H), 2.69-2.58 (m, 2H), 2.52 (s, 3H),2.20-2.11 (s, 2H), 1.68-1.56 (m, 2H). LCMS (4 min) Rt=1.32 min; m/z(ESI⁺) 416 (MH⁺).

Synthesis 1625-(5-(4-(2-Methoxyethoxy)phenyl)-4-(1-methylpiperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-117)

The title compound was prepared from the product of Synthesis 155-Cusing methods analogous to those described in Synthesis 167, steps 167-Cand 167-D.

¹H NMR (500 MHz, MeOD) δ 8.93 (m, 1H). 8.55 (s, 1H), 7.73 (s, 1H), 7.31(d, 2H, J=8.5 Hz), 7.06 (s, 1H), 7.08 (2H, d, J=8.5 Hz), 4.20-4.17 (m,2H), 3.80-3.77 (m, 2H), 3.45 (s, 3H), 2.87-2.76 (m, 2H), 2.31 (s, 3H),2.35-2.23 (s, 2H), 2.09-2.01 (m, 2H), 1.57-1.46 (m, 2H). LCMS (4)Rt=1.95 min; m/z (ESI⁺) 460 (MH⁺).

Synthesis 1635-(5-(3-(2-methoxyethoxy)phenyl)-4-(1-methylpiperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-118)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 156, steps 156-A and 156-B.

¹H NMR (500 MHz, MeOD) δ 8.93 (s, 1H), 8.55 (s, 1H), 7.78 (s, 1H), 7.42(t, 1H, J=8.0 Hz), 7.10 (s, 1H), 7.03-6.95 (m, 3H), 4.19-4.16 (m, 2H),3.79-3.76 (m, 2H), 3.57-3.49 (m, 1H), 3.44 (s, 3H), 2.98-2.87 (m, 2H),2.50-2.40 (m, 2H), 2.42 (s, 3H), 2.14-2.07 (m, 2H), 1.62-1.52 (m, 2H).LCMS (4) Rt=1.60 min; m/z (ESI⁺) 460 (MH⁺).

Synthesis 1645-(5-(4-(Methoxymethyl)phenyl)-4-(1-methylpiperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-119)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 156, steps 156-A and 156-B.

¹H NMR (CDCl₃, 500 MHz) δ 8.74 (s, 1H), 8.46 (s, 1H), 7.82 (s, 1H),7.48-7.45 (m, 2H), 7.38-7.36 (m, 2H), 7.16 (s, 1H), 4.54 (s, 2H),3.48-3.39 (m, 2H), 2.79-2.77 (m, 2H), 2.33 (s, 3H), 2.21-2.19 (m, 2H),2.08-2.06 (m, 2H), 1.57-1.50 (m, 2H). LCMS (4) R_(t) 1.32 min; m/z(ESI⁺) 430 [MH⁺].

Synthesis 1655-(4-(1-Methylpiperidin-4-ylamino)-5-(4-morpholinophenyl)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-120)

The title compound was prepared from the product of Synthesis 155-Cusing methods analogous to those described in Synthesis 167, steps 167-Cand 167-D.

¹H NMR (500 MHz, MeOD) δ 8.90 (s, 1H), 8.54 (s, 1H), 7.73 (s, 1H), 7.28(d, 2H, J=8.5), 7.09 (d, 2H, J=8.5), 7.05 (s, 1H), 3.78-3.85 (m, 4H),3.53-3.45 (m, 1H), 3.24-3.20 (m, 4H), 2.91-2.81 (m, 2H), 2.39-2.30 (m,2H), 2.35 (s, 3H), 2.11-2.04 (m, 2H), 1.58-1.47 (m, 2H). LCMS (4)Rt=2.00 min; m/z (ESI⁺) 471 (MH⁺).

Synthesis 1665-(4-(1-Methylpiperidin-4-ylamino)-5-o-tolylpyridin-2-ylamino)pyrazine-2-carbonitrile(Y-121)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 156, steps 156-A and 156-B.

¹H NMR (MeOD-d₄, 500 MHz) δ 8.94 (s, 1H), 8.55 (d, 1H, J=1.4 Hz), 7.67(s, 1H), 7.36-7.31 (m, 3H), 7.18-7.16 (m, 1H), 7.09 (s, 1H), 3.49-3.45(m, 1H), 2.81-2.79 (m, 2H), 2.34-2.32 (m, 2H), 2.17 (s, 3H), 2.05-1.98(m, 2H), 1.50-1.38 (m, 2H). LCMS (4) R_(t) 1.65 min; m/z (ESI⁺) 400[MH⁺].

Synthesis 167-A Benzyl4-(5-bromo-2-pivalamidopyridin-4-ylamino)piperidine-1-carboxylate

N-(5-Bromo-4-chloropyridin-2-yl)pivalamide (Synthesis 155-A) (1.08 g,3.70 mmol), benzyl 4-aminopiperidine-1-carboxylate (1.736 g, 7.41 mmol),and triethylamine (1.041 mL, 7.41 mmol) in NMP (7.41 mL) in a sealedvial was heated to 210° C. by microwave irradiation for 1.5 hr. Thecooled solution was diluted with MeOH and purified by ion exchange onIsolute SCX II acidic resin eluting with MeOH then 2M NH₃ in MeOH. Hebasic fractions were combined and volatiles were removed in vacuo. Thecrude product was dissolved in dichloromethane and loaded onto a Biotagesilica column. Flash column chromatography eluting with a gradient ofEtOAc in hexanes gaveN-(5-bromo-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide (0.536g, 1.095 mmol, 30%) as a clear glass.

¹H NMR (500 MHz, CDCl₃) δ 8.03 (s, 1H), 7.95 (s, 1H), 7.69 (s, 1H),7.39-7.30 (m, 5H), 5.15 (s, 2H), 4.74 (d, 1H, J=7.7 Hz), 4.13 (q, 3H,J=7.0 Hz), 3.73-3.64 (m, 1H), 3.12 (t, 2H, J=11.5 Hz), 2.13-2.06 (m,2H), 1.54-1.43 (m, 2H), 1.33 (s, 9H). LCMS (4) Rt=2.48 min; m/z (ESI⁺)489/491 (MH⁺).

Synthesis 167-B tert-Butyl4-(2-amino-5-bromopyridin-4-ylamino)piperidine-1-carboxylate

N-(5-Bromo-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide (526mg, 1.075 mmol) in 6M HCl (10 mL, 60.0 mmol) was heated by microwaveirradiation to 105° C. for 1.5 hr. After cooling the volatiles wereremoved in vacuo. The residue was purified by ion exchange on IsoluteSCX II acidic resin, washing with MeOH and then with 2M NH₃ in MeOH. Thebasic fractions were concentrated to give crude5-bromo-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine (290 mg, 1.069mmol, 100% yield) as a cream powder. LCMS (4) Rt=0.56 min; m/z (ESI⁺)271/273 (MW). Di-tert-butyl dicarbonate (73.6 μl, 0.317 mmol) dissolvedin the minimum amount of dichloromethane was slowly added to anice-cooled solution of 5-bromo-N4-(piperidin-4-yl)pyridine-2,4-diamine(86 mg, 0.317 mmol) in triethylamine (134 μL, 0.951 mmol) anddichloromethane (2.44 mL). The mixture was stirred at 0° C. for 30 minfollowed by 1 hr at r.t. Solvents were removed in vacuo and the crudematerial was purified by preparative thin layer chromatography, elutingwith 7% MeOH, 1% NH3 in dichloromethane, to give tert-butyl4-(2-amino-5-bromopyridin-4-ylamino)piperidine-1-carboxylate (91 mg,0.245 mmol, 77%) as a colourless foam.

¹H NMR (500 MHz, CDCl₃) δ 7.82 (s, 1H), 5.69 (s, 1H), 4.51 (d, 1H, J=7.5Hz 4.31 (br s, 2H), 4.05-3.91 (m, 2H), 3.41.3.32 (m, 1H), 2.98-2.86 (m,2H), 1.99-1.90 (m, 1H), 1.44 (s, 9H), 1.44-1.36 (m, 1H). LCMS (4)Rt=1.87 min; m/z (ESI⁺) 371/373 (MH⁺).

Synthesis 167-C tert-Butyl4-(2-amino-5-(4-methoxyphenyl)pyridin-4-ylamino)piperidine-1-carboxylate

Acetonitrile (1212 μL) and 0.5M sodium carbonate solution (0.36 mL, 1.5eq) were added to tert-butyl4-(2-amino-5-bromopyridin-4-ylamino)piperidine-1-carboxylate (45 mg,0.121 mmol), 4-methoxyphenylboronic acid (27.6 mg, 0.182 mmol), andtetrakis(triphenylphosphine)palladium(0) (7.00 mg, 6.06 μmol) in amicrowave vial (0.5 mL). The capped vial was heated to 150° C. bymicrowave irradiation for 20 min. After cooling the solution was dilutedwith MeOH and purified by ion exchange on SCX-II acidic resin (2 g)column, eluting with MeOH then 2M ammonia in MeOH. The basic fractionswere combined and concentrated. The crude product was dissolved indichloromethane and loaded onto a Biotage SNAP silica column (10 g)which was eluted with a gradient of MeOH/NH₃ (99/1) in dichloromethaneto give tert-butyl4-(2-amino-5-(4-methoxyphenyl)pyridin-4-ylamino)piperidine-1-carboxylate(19 mg, 0.048 mmol, 39%) as a colourless foam.

¹H NMR (500 MHz, CDCl₃) δ 7.60 (s, 1H), 7.23 (d, 2H, J=8.5 Hz), 6.97 (d,2H, J=8.5 Hz), 5.75 (s, 1H), 4.45 (br s, 2H), 4.20 (d, 1H, J=7.5 Hz),3.98-3.88 (m, 2H), 3.85 (s, 3H), 3.47-3.39 (m, 1H), 2.96 (t, 2H, J=11.0Hz), 1.99-1.92 (m, 2H), 1.45 (s, 9H), 1.34-1.24 (m, 2H). LCMS (4)Rt=2.20 min; m/z (ESI⁺) 399 (MH⁺).

Synthesis 167-D tert-butyl4-(2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)piperidine-1-carboxylate

Dry DME (402 μL) was added to a mixture of tert-butyl4-(2-amino-5-(4-methoxyphenyl)pyridin-4-ylamino)piperidine-1-carboxylate(16 mg, 0.040 mmol), 5-bromopyrazine-2-carbonitrile (7.39 mg, 0.040mmol), xantphos (1.859 mg, 3.21 μmol),tris(dibenzylideneacetone)dipalladium(0) (1.471 mg, 1.606 μmol), andcesium carbonate (26.2 mg, 0.080 mmol) in a nitrogen purged, sealedmicrowave vial. Nitrogen gas was bubbled through the mixture for 5 min.The reaction mixture was heated for 1 hr at 100° C. by microwaveirradiation. Upon cooling the mixture was diluted with MeOH and purifiedby ion exchange on Isolute SCX II acidic resin (5 g), eluting with MeOH.The eluent was concentrated and further purified by preparative thinlayer chromatography, eluting with 7% MeOH, 1% NH3, 92% DCM, to give5-(5-(4-methoxyphenyl)-4-(1-methylpiperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(4 mg, 7.97 μmol, 20% yield) as a light yellow powder.

¹H NMR (500 MHz, CDCl₃) δ 8.83 (s, 1H), 8.46 (s, 1H), 7.77 (s, 1H), 7.29(d, 2H, J=8.5 Hz), 7.15 (s, 1H), 7.05 (d, 2H, J=8.5 Hz), 4.62 (d, 1H,J=7.0 Hz), 4.05-3.94 (m, 2H), 3.90 (s, 3H), 3.65-3.55 (m, 1H), 3.08-2.97(m, 2H), 2.08-2.00 (d, 2H, J=12.5 Hz), 1.43 (s, 9H), 1.43-1.32 (m, 2H).LCMS (4) Rt=2.36 min; m/z (ESI⁺) 502 (MH⁺).

Synthesis 167-E5-(5-(4-Methoxyphenyl)-4-(piperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-122)

Trifluoroacetic acid (0.1 μL, 1.298 μmol) was added to tert-butyl4-(2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)piperidine-1-carboxylate(4 mg, 7.97 μmol) dissolved in dichloromethane (0.45 mL) and the mixturewas stirred for 1 hr. The mixture was concentrated and purified by ionexchange on Isolute SCX II acidic resin (1 g), eluting with MeOH then 2MNH₃—MeOH. The basic fractions were combined and concentrated.Preparative thin layer chromatography, eluting with 10% MeOH/1% NH₃/89%dichloromethane) gave5-(5-(4-methoxyphenyl)-4-(piperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(2 mg, 4.98 μmol, 62.5% yield) as a yellow powder.

¹H NMR (500 MHz, MeOD) δ 8.93 (s, 1H), 8.56 (s, 1H), 7.74 (s, 1H), 7.32(d, 2H, J=9.0 Hz), 7.07 (d, 2H, J=9.0 Hz), 7.07 (s, 1H), 3.87 (s, 3H),3.61-3.53 (s, 1H), 3.10-3.03 (m, 2H), 2.79-2.72 (m, 2H), 2.10-2.02 (m,2H), 1.43-1.32 (m, 2H). LCMS (4) Rt=1.97 min; m/z (ESI⁺) 402 (MH⁺).

Synthesis 168-A(E)-5-(3-Methoxyprop-1-enyl)-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine

A solution of 5-bromo-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine(Synthesis 155-C) (0.100 g, 0.35 mmol), sodium carbonate (0.5 M, 1.05mL) and tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.02 mmol) inacetonitrile (3.40 mL) was heated for 20 min at 130° C. by microwaveirradiation. The reaction mixture was concentrated in vacuo. The crudeproduct was purified by ion exchange on SCX-II acidic resin (1 g)eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol.The basic fractions were combined and the solvent was removed in vacuo.The crude mixture was used without further purification.

¹H NMR (CDCl₃, 500 MHz) δ 7.68 (s, 1H), 6.35 (d, 1H, J=15.7 Hz), 5.98(dt, 1H, J=5.8, 15.7 Hz), 5.67 (s, 1H), 4.03 (d, 2H, J=7.2 Hz), 3.36 (s,3H), 3.32-3.18 (m, 1H), 2.86-2.67 (m, 2H), 2.27 (s, 3H), 2.10 (t, 2H,J=10.5 Hz), 2.06-1.92 (m, 2H), 1.51 (td, 2H, J=3.6, 13.6 Hz). LCMS (4)R_(t) 0.82 min; m/z (ESI⁺) 277 [MH⁺].

Synthesis 168-B(E)-5-(5-(3-methoxyprop-1-enyl)-4-(1-methylpiperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-123)

A solution of(E)-5-(3-methoxyprop-1-enyl)-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine(0.090 g, 0.32 mmol), 2-bromo-cyanopyrazine (0.060 g, 0.32 mmol), BINAP(0.007 g, 0.02 mmol), sodium tert-butoxide (0.043 g, 0.45 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (0.013 g, 0.01mmol) in dioxane (3 mL) was stirred at room temperature under nitrogenfor 10 min, then heated for 30 min at 90° C. under microwaveirradiation. The crude reaction mixture was purified by ion exchange onSCX-II acidic resin (1 g) eluting with methanol/dichloromethane (1/1),then 2M ammonia-methanol. The basic fractions were combined and thesolvent was removed in vacuo. The crude mixture was purified bypreparative thin layer chromatography, eluting withmethanol/dichloromethane (1/9), to give the title compound as a yellowsolid (0.004 g, 3%).

¹H NMR (CDCl₃, 500 MHz) δ 8.81 (s, 1H), 8.76 (s, 1H), 8.44 (m, 1H), 7.93(s, 1H), 7.02 (s, 1H), 6.45 (d, 1H, J=15.8 Hz), 6.15 (1H, dt, J=15.8,5.5 Hz), 4.40 (d, 1H, J=7.2 Hz), 4.12 (2H, J=5.5, 1.5 Hz), 3.45 (s, 3H),2.90-2.88 (m, 2H), 2.37 (s, 3H), 2.23 (t, 2H, J=11.1 Hz), 2.14-2.11 (m,2H), 1.66-1.64 (m, 2H). LCMS (4) R_(t) 1.72 min; m/z (ESI⁺) 380 [MH⁺].

Synthesis 169-A Benzyl4-((5-chloro-2-pivalamidopyridin-4-ylamino)methyl)piperidine-1-carboxylate

A capped microwave reaction vial containing a solution ofN-(4,5-dichloropyridin-2-yl)pivalamide (0.38 g, 1.54 mmol) (Synthesis153-B), benzyl 4-(aminomethyl)piperidine-1-carboxylate (0.76 g, 2 eq)and triethylamine (0.43 mL, 2 eq) in NMP (3 mL) was heated at 210° C.for 1.75 hr under microwave irradiation, and then allowed to cooled. Thereaction mixture was diluted with MeOH and adsorbed onto Isolute SCX-IIacidic resin (10 g). The resin was washed with methanol, then 2M ammoniain methanol. The basic fractions were concentrated and the crude productwas further purified by column chromatography, using a Biotage 40+silicacolumn eluted with a gradient of EtOAc in hexane. The product containedresidual NMP which was removed by a second ion exchange purification onIsolute SCX-II acidic resin, eluting with methanol, then 2M ammonia inmethanol, to give benzyl4-((5-chloro-2-pivalamidopyridin-4-ylamino)methyl)piperidine-1-carboxylateas a light yellow gum (0.53 g, 68%).

¹H NMR (500 MHz, MeOD) δ 7.91 (s, 1H), 7.86 (br s, 1H), 7.67 (s, 1H),7.39-7.30 (m, 5H), 5.15 (s, 2H), 4.83 (t, 1H, J=5.5 Hz), 4.25 (br s,2H), 3.20 (dd, 2H, J=6.0, 6.0 Hz), 2.89-2.76 (m, 2H), 1.87-1.76 (m, 2H,1H), 1.31-1.18 (m, 2H). LCMS (3B) Rt=4.19 min; m/z (ESI⁺) 459 (MH⁺).

Synthesis 169-B tert-Butyl4-((2-amino-5-chloropyridin-4-ylamino)methyl)piperidine-1-carboxylate

Benzyl4-((5-chloro-2-pivalamidopyridin-4-ylamino)methyl)piperidine-1-carboxylate(0.52 g, 1.12 mmol) was refluxed in 6M HCl (20 mL) for 2 hr. Thevolatiles were removed in vacuo and the residue was dissolved in MeOHand adsorbed onto Isolute SCX-II acidic resin. The resin was washed withmethanol, then 2M ammonia in methanol. The basic fractions wereconcentrated to give crude5-chloro-N4-(piperidin-4-ylmethyl)pyridine-2,4-diamine (0.234 g, 96%).LCMS (4) Rt=0.51 min; m/z (ESI⁺) 241 (MH⁺). Di-tert-butyl dicarbonate(0.21 g, 1 eq.) in dichloromethane (1 mL) was added dropwise to5-chloro-N4-(piperidin-4-ylmethyl)pyridine-2,4-diamine (0.228 g, 0.95mmol) and triethylamine (0.40 ml, 3 eq.) in dichloromethane (6.5 mL).The solution was stirred at room temperature for 2 hr. Solvents wereevaporated and the crude product was purified by preparative thin layerchromatography, eluting with 8% MeOH, 1% NH₃, 91% dichloromethane, togive tert-butyl4-((2-amino-5-chloropyridin-4-ylamino)methyl)piperidine-1-carboxylate(109 mg, 34%) as a white powder.

¹H NMR (500 MHz, CDCl₃) δ 7.69 (s, 1H), 5.65 (s, 1H), 4.68 (t, 1H, J=5.5Hz), 4.44 (br s, 2H), 4.10 (br s, 2H), 2.98 (dd, 2H, J=6.0, 6.0 Hz),2.73-2.60 (m, 2H), 1.76-1.65 (m, 1H, 2H), 1.47 (s, 9H), 1.20-1.05 (m,2H), LCMS (4) Rt=1.95 min; m/z (ESI⁺) 341 (MH⁺).

Synthesis'169-C tert-Butyl4-((5-chloro-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

Dry dioxane (0.45 mL) was added to a microwave reaction vial containingtert-butyl4-((2-amino-5-chloropyridin-4-ylamino)methyl)piperidine-1-carboxylate(23 mg, 0.067 mmol), 5-bromopyrazine-2-carbonitrile (8.3 mg, 0.045mmol), tris(dibenzylideneacetone)-dipalladium chloroform complex (1.9mg, 4 mol%), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (2.2 mg,8 mol%) and sodium tert-butoxide (6.1 mg, 1.4 eq.) under nitrogen. Thevial was sealed and nitrogen gas was bubbled through the suspension withstirring for 5 min. The mixture was heated at 90° C. for 30 min undermicrowave irradiation. The mixture was diluted with methanol andadsorbed onto Isolute SCX-II acidic resin (2 g). The resin was washedwith methanol, then 2M ammonia in methanol. The basic fractions wereconcentrated and the residue was further purified by preparative thinlayer chromatography, eluting with 5% MeOH in dichloromethane, to givetert-butyl4-((5-chloro-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(12 mg, 60%) as an off-white solid.

¹H NMR (500 MHz, CDCl₃) δ 8.80 (s, 1H), 8.47 (s, 1H), 8.19 (br s, 1H),8.00 (s, 1H), 7.09 (s, 1H), 4.99 (dd, 1H, J=5.5, 5.5 Hz), 4.20 (br s,2H), 3.20 (dd, 2H, J=6.0, 6.0 Hz), 2.79-2.69 (m, 2H), 1.91-1.76 (m, 1H,2H), 1.48 (s, 9H), 1.31-1.21 (m, 2H). LCMS (4) Rt=2.21 min; m/z (ESI⁺)444 (MH⁺).

Synthesis 169-D5-(5-chloro-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-124)

Trifluoroacetic acid (0.1 mL) was added to tert-butyl4-((5-chloro-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(12 mg, 0.027 mmol) in dichloromethane (1 mL) and the mixture wasstirred at r.t. for 2 hr. Solvent was removed in vacuo and the residuewas redissolved in MeOH and adsorbed onto Isolute SCX-II acidic resin(500 mg). The resin was washed with methanol, then 2M ammonia inmethanol. The basic fractions were evaporated to dryness to give5-(5-chloro-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(2 mg, 22%) as a yellow powder.

¹H NMR (500 MHz, MeOD) δ 8.89 (d, 1H, J=1.5 Hz), 8.57 (d, 1H, J=1.5 Hz),7.92 (s, 1H), 7.19 (s, 1H), 3.19 (d, 2H, J=6.5 Hz), 3.16-3.10 (m, 2H),2.69-2.61 (m, 2H), 1.94-1.80 (m, 1H, 2H), 1.35-1.24 (m, 2H). LCMS (4)Rt=1.03 min; m/z (ESI⁺) 344 (MH⁺).

Synthesis 170-A 2-Chloro-5-iodopyridin-4-amine

Iodine monochloride (0.758 g, 4.67 mmol) was added to a solution of2-chloro-4-amino pyridine (0.500 g, 3.89 mmol) and potassium acetate(0.763 g, 7.78 mmol) in acetic acid (30 mL). The reaction mixture washeated under reflux for 4 hr. The solvent was removed in vacuo and theresidue was partitioned between aqueous sodium hydrogenocarbonate (50mL) and ethyl acetate (50 mL). The organic phase was dried (MgSO₄) andthe solvent was removed in vacuo. The crude product was purified byflash silica chromatography, eluting with ethyl acetate and hexane(1/9), to give the title compound as a pink solid (0.394 g, 40%).

¹H NMR (CDCl₃, 500 MHz) δ 8.33 (s, 1H), 6.63 (s, 1H), 4.85 (brs, 2H).LCMS (4) R_(t) 1.66 min; m/z (ESI⁺) 254 [MH⁺].

Synthesis 170-B tert-Butyl4-((2-chloro-5-iodopyridin-4-ylamino)methyl)piperidine-1-carboxylate

NaH (0.098 g, 3.9 mmol) was added to a solution of2-chloro-5-iodopyridin-4-amine (0.500 g, 1.96 mmol) in DMF (12 mL) andthe mixture was stirred for 30 min at r.t. The temperature was thenraised to 80° C. and a solution of tert-butyl4-(bromomethyl)-piperidine-1-carboxylate (1.093 g, 3.93 mmol) in DMF (2mL) was added. The reaction mixture was stirred at 80° C. for 2 h, thencooled to r.t. NaH (0.050 g, 2.00 mmol) was added and the reactionmixture was heated for 1 h at 80° C. After cooling, water (40 mL) wasadded and the reaction mixture was partitioned between ethyl acetate andaq. NaHCO₃. The organic phase was washed with brine, dried (MgSO₄) andconcentrated. The crude product was purified by flash silicachromatography, eluting with ethyl acetate and hexane (1/9), to give thetitle compound as a pink solid (0.405 g, 46%).

¹H NMR (CDCl₃, 500 MHz) δ 8.28 (s, 1H), 6.41 (s, 1H), 4.85 (t, 1H, J=5.2Hz), 4.27-4.08 (m, 2H), 3.12 (t, 2H, J=6.2 Hz), 2.76-2.71 (m, 2H),1.88-1.70 (m, 3H), 1.47 (s, 9H), 1.29-1.13 (m, 2H); LCMS (4) R_(t) 2.78min; m/z (ESI⁺) 395 [MH⁺].

Synthesis 170-C tert-Butyl4-((2-chloro-5-phenylpyridin-4-ylamino)methyl)piperidine-1-carboxylate

A solution of tert-butyl4-((2-chloro-5-iodopyridin-4-ylamino)methyl)piperidine-1-carboxylate(0.100 g, 0.22 mmol), sodium carbonate (0.5 M, 0.66 mL), phenyl boronicacid (0.027 g, 0.221 mmol) and tetrakis(triphenylphosphine) palladium(0)(0.011 g, 0.01 mmol) in acetonitrile (2 mL) was heated at 100° C. for 20min under microwave irradiation. The reaction mixture was concentratedin vacuo. The crude product was purified by chromatography on a shortsilica column, eluting with ethyl acetate/petroleum ether (3/7), to givethe title compound as a colourless oil (0.088 g, 98%).

¹H NMR (CDCl₃, 500 MHz) δ 7.83 (s, 1H), 7.51-7.48 (m, 2H), 7.44-7.41 (m,1H), 7.36-7.32 (m, 2H), 6.52 (s, 1H), 4.57 (t, 1H, J=5.7 Hz), 4.19-4.02(m, 2H), 3.03 (t, 2H, J=6.3 Hz), 2.68 (t, 2H, J=11.9 Hz), 1.75-1.68 (m,1H), 1.66-1.63 (m, 2H), 1.45 (s, 9H), 1.16-1.08 (m, 2H). LC-MS (4) R_(t)2.71 min; m/z (ESI⁺) 402 [MH⁺].

Synthesis 170-D tert-Butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-phenylpyridin-4-ylamino)methyl)piperidine-1-carboxylate

A solution of tert-butyl4-((2-chloro-5-phenylpyridin-4-ylamino)methyl)piperidine-1-carboxylate(0.040 g, 0.100 mmol), 2-amino-4-cyanopyrazine (0.018 g, 0.149 mmol),Xantphos (0.009 g, 0.016 mmol), cesium carbonate (0.065 g, 0.19 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (0.007 g, 0.008mmol) in dioxane (0.7 mL) was stirred at r.t. under nitrogen for 10 min,then heated under microwave irradiation for 60 min at 150° C. Thereaction mixture was purified by ion exchange on SCX-II acidic resin (1g), eluting with methanol/dichloromethane (1/1), then 2Mammonia-methanol. The basic fractions were combined and solvent wasremoved in vacuo. The crude product was purified by preparative thinlayer chromatography, eluting with ethyl acetate/hexane (1/1), to givethe title compound as a yellow solid (0.020 g, 41%).

¹H NMR (CDCl₃, 500 MHz) δ 8.67 (s, 1H), 8.46 (s, 1H), 7.84 (s, 1H), 7.52(t, 2H, J=7.4 Hz), 7.44 (t, 1H, J=7.4 Hz), 7.38 (d, 2H, J=7.0 Hz), 7.28(s, 1H), 7.21 (s, 1H), 4.71 (t, 1H, J=5.7 Hz), 3.11 (t, 2H, J=6.2 Hz),2.78-2.62 (m, 2H), 1.79-1.82 (m, 1H), 1.69 (d, 2H, J=12.4 Hz), 1.47 (s,9H), 1.27 (t, 2H, J=7.1 Hz), 1.13-1.18 (m, 2H). LCMS (4) R_(t) 2.18 min;m/z (ESI⁺) 486 [MH⁺].

Synthesis 170-E tert-Butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-phenylpyridin-4-ylamino)methyl)piperidine-1-carboxylate(Y-125)

TFA (0.2 mL) was added at room temperature to a solution of tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-phenylpyridin-4-ylamino)methyl)piperidine-1-carboxylate(0.020 g, 0.041 mmol) in dichloromethane (2 mL). The reaction mixturewas stirred for 20 min. Solvent was removed in vacuo and the mixture waspurified by ion exchange on SCX-II acidic resin (500 mg), eluting withmethanol, then 2M ammonia-methanol. The basic fractions were combinedand solvent was removed in vacuo. The crude product was purified bypreparative thin layer chromatography, eluting withmethanol/dichloromethane/NH₃ (0.9/9/0.01), to give the title compound asa yellow solid (0.012 g, 76%).

¹H NMR (MeOD-d₄, 500 MHz) 8.90 (s, 1H), 8.56 (s, 1H), 7.73 (s, 1H),7.51-7.40 (m, 5H), 7.11 (s, 1H), 3.15-3.12 (m, 4H), 2.66 (t, 2H, J=13.5Hz), 1.92-1.78 (m, 3H), 1.33-1.22 (m, 2H). LCMS (4) R 1.24 min; m/z(ESI⁺) 386 [MH⁺].

Synthesis 171-A Benzyl4-((5-bromo-2-pivalamidopyridin-4-ylamino)methyl)piperidine-1-carboxylate

Two capped microwave reaction vials each containing a solution ofN-(5-bromo-4-chloropyridin-2-yl)pivalamide (0.55 g, 1.89 mmol), benzyl4-(aminomethyl)piperidine-1-carboxylate (1.07 g, 2 eq.) andtriethylamine (0.80 mL, 3 eq.) in NMP (3.8 mL) were heated at 210° C. bymicrowave irradiation for 1.5 hr and then allowed to cool. The contentsof the two vials were combined and partitioned between EtOAc (15 mL) andsat. NaHCO₃ (150 mL). The organic layer was retained whilst the aqueouswas further extracted with EtOAc (15 mL). The organic extracts werecombined, washed with brine (50 mL), dried (MgSO₄) and concentrated. Thecrude material was purified by chromatography on a 40+M Biotage silicacolumn, eluting with a gradient of EtOAc in dichloromethane, to give thetitle compound as a clear oil (0.83 g, 43%)

¹H NMR (500 MHz, CDCl₃) δ 8.01 (s, 1H), 7.87 (s, 1H), 7.65 (s, 1H),7.39-7.35 (m, 4H), 7.34-7.30 (m, 1H), 5.14 (s, 2H), 4.86 (t, 1H, J=5.5Hz), 4.25 (br s, 2H), 3.19 (t, 2H, J=6.0 Hz), 2.88-2.77 (m, 2H),1.92-1.76 (m, 2H, 1H), 1.32 (s, 9H), 1.30-1.19 (m, 2H). LCMS (3.5 min)Rt=2.42 min; m/z (ESI⁺) 503/505 (MH⁺).

Synthesis 171-B tert-Butyl4-((2-amino-5-bromopyridin-4-ylamino)methyl)piperidine-1-carboxylate

A mixture of benzyl4-((5-bromo-2-pivalamidopyridin-4-ylamino)methyl)piperidine-1-carboxylate(0.695 g, 1.24 mmol) and 6M HCl (10 mL) was heated at 105° C. for 45mins by microwave irradiation. After cooling the volatiles were removedin vacuo. The residue was redissolved in MeOH and adsorbed onto (soluteSCX-II acidic resin. The resin was washed with methanol, then 2M ammoniain methanol. The basic fractions were concentrated to give crude5-bromo-N4-(piperidin-4-ylmethyl)pyridine-2,4-diamine (0.326 g, 92%),LCMS (4) Rt=0.51 min; m/z (ESI⁺) 285/287 (MH⁺). A solution ofdi-tert-butyl dicarbonate (0.249 g, 1 eq.) in dichloromethane (1 mL) wasadded dropwise to an ice-cooled solution of5-bromo-N4-(piperidin-4-ylmethyl)pyridine-2,4-diamine (0.326 g, 1.14mmol) and triethylamine (0.48 mL, 3 eq.) in dichloromethane (7.79 mL).The solution was stirred at 0° C. for 30 mis and then warmed to roomtemperature and stirred for a further 30 min. The mixture wasconcentrated. The crude product was purified by preparative TLC, elutingwith 7% MeOH, 1% NH₃, 92% dichloromethane, to give tent-butyl4-((2-amino-5-bromopyridin-4-ylamino)methyl)piperidine-1-carboxylate(234 mg, 53%) as a white powder.

¹H NMR (500 MHz, CDCl₃) δ 7.86 (s, 1H), 5.68 (s, 1H), 4.74-6.68 (m, 1H),4.40-4.07 (m, 4H), 3.05 (dd, 2H, J=6.0, 6.0 Hz), 2.84-2.63 (m, 2H),1.83-1.72 (m, 2H,1H), 1.47 (s, 9H), 1.25-1.14 (m, 2H). LCMS (4) Rt=1.90min; m/z (ESI⁺) 385/387 (MH⁺).

Synthesis 171-C tert-Butyl4-((2-amino-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

Two capped 0.5 mL microwave reaction vials each containing a solution oftert-butyl4-((2-amino-5-bromopyridin-4-ylamino)methyl)piperidine-1-carboxylate (30mg, 0.078 mmol), 4-methoxyphenyl boronic acid (17.8 mg, 1.5 eq.),Pd(PPh₃)₄ (4.5 mg, 5 mol %), 0.5M aqueous sodium carbonate (0.23 mL, 1.5eq.) in acetonitrile (0.78 mL) were heated at 150° C. for 20 min bymicrowave irradiation. After cooling, the contents of the two reactionvials were combined and solvents were removed in vacuo. The crudeproduct was purified by chromatography using a Biotage SNAP silica (10g) column, eluting with a gradient of methanol/NH₃ (99/1) indichloromethane, to give the title compound as a yellow solid (48 mg,75%).

¹H NMR (500 MHz, CDCl₃) δ 7.53 (s, 1H), 7.21 (d, 2H, J=8.5), 6.96 (d,2H, J=8.5), 5.75 (s, 1H), 4.92 (br s, 2H), 4.40 (t, 1H, J=6.0 Hz), 4.10(br s, 2H), 3.83 (s, 3H), 2.97 (dd, 2H, J=6.0, 6.0 Hz), 2.70-2.59 (m,2H), 1.75-1.59 (m, 1H+2H), 1.44 (s, 9H), 1.14-1.03 (m, 2H). LCMS (4)Rt=2.15 min; m/z (ESI⁺) 413 (MH⁺).

Synthesis 171-D tert-Butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

Dry DME (0.87 mL) was added to a microwave reaction vial containingtert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(36 mg, 0.087 mmol), 5-bromopyrazine-2-carbonitrile (19 mg, 0.105 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (3.6 mg, 4 mol%), Xantphos (4.0 mg, 8 mol %) and cesium carbonate (57 mg, 2 eq.) undernitrogen. The vial was sealed and nitrogen was bubbled through thestirred suspension for 10 min. The mixture was heated at 100° C. for 1hr by microwave irradiation. The mixture was diluted with methanol andadsorbed onto (solute SCX-II acidic resin (2 g). The resin was washedwith methanol, then 2M ammonia in methanol. The basic fractions wereconcentrated and further purified by preparative thin layerchromatography, eluting with 5% MeOH, 0.5% NH₃, 94.5% dichloromethane,to give the title compound as a yellow solid (15 mg, 33%).

¹H NMR (500 MHz, MeOD) δ 8.86 (s, 1H), 8.55 (s, 1H), 7.69 (s, 1H), 7.31(d, 2H, J=9.0 Hz), 7.06 (d, 2H, J=9.0 Hz), 7.01 (s, 1H), 4.13-4.08 (m,2H), 3.86 (s, 3H), 3.33-3.30 (m, 1H), 3.11 (d, 2H, J=7.0 Hz), 2.74 (brs, 2H), 1.94-1.83 (m, 1H), 1.77-1.69 (m, 2H), 1.46 (s, 9H), 1.19-1.08(m, 2H). LCMS (4) Rt=2.22 min; m/z (ESI⁺) 516 (MH⁺).

Synthesis 171-E5-(5-(4-Methoxyphenyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-126)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 169, step 169-D.

¹H NMR (500 MHz, MeOD) δ 8.85 (s, 1H), 8.58 (d, 1H, J=1.4 Hz), 7.71 (s,1H), 7.31 (d, 2H, J=8.5 Hz), 7.14 (s, 1H), 7.06 (d, 2H, J=8.5 Hz), 3.86(s, 3H), 3.32-3.26 (m, 2H), 3.16 (d, 2H, J=6.5 Hz), 2.89-2.80 (m, 2H),2.01-1.87 (s, 2H +1H), 1.42-1.29 (s, 2H). LCMS (4) Rt=1.33 min; m/z(ESI⁺) 416 (MH⁺).

Synthesis 1725-(5-(4-(Methoxymethyl)phenyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-127)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 171, steps 171-A, 171-B, 171-C, 171-D and 171-E.

¹H NMR (MeOD-d₄, 500 MHz) δ 8.90 (s, 1H), 8.56 (s, 1H), 7.73 (s, 1H),7.48 (d, 2H, J=8.1), 7.40 (d, 2H, J=8.1), 7.11 (s, 1H), 4.84 (m, 3H),4.53 (s, 2H), 3.33 (t, 1H, J=3.3), 3.11-3.09 (m, 4H), 2.65 (dt, 2H,J=12.4, 2.5 Hz), 1.94-1.71 (m, 2H), 1.38-1.18 (m, 2H). LCMS (4) Rt=1.34min; m/z (ESI⁺) 430 [MH⁺].

Synthesis 173 Ethyl4-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)thiophene-2-carboxylate(Y-128)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 171, steps 171-A, 171-B, 171-C, 171-D and 171-E.

¹H NMR (500 MHz, MeOD) δ 8.91 (d, 1H, J=1.5 Hz), 8.57 (d, 1H, J=1.5 Hz),7.86 (d, 1H, J=1.5 Hz), 7.83 (s, 1H), 7.77 (d, 1H, J=1.5 Hz), 7.17 (s,1H), 4.38 (q, 2H, J=7.0 Hz), 3.38-3.33 (m, 2H), 3.19 (d, 2H, J=6.5 Hz),2.90 (td, 2H, J=3.0, 13.0 Hz), 2.06-1.94 (m, 2H, 1H), 1.49-1.40 (m, 2H),1.39 (t, 4H, J=7.0 Hz). LCMS (4) Rt=1.42 min; m/z (ESI⁺) 464 (MH⁺).

Synthesis 1745-(5-(4-(2-hydroxyethoxy)phenyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-129)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 171, steps 171-A, 171-B, 171-C, 171-D and 171-E.

¹H NMR (500 MHz, MeOD) δ 8.86 (d, 1H, J=1.0 Hz), 8.55 (d, 1H, J=1.0 Hz),7.69 (s, 1H), 7.30 (d, 2H, J=8.5 Hz), 7.09 (d, 2H, J=8.5 Hz), 7.07 (s,1H), 4.11 (t, 2H, J=5.0 Hz), 3.91 (t, 2H, J=5.0 Hz), 3.11 (d, 4H, J=6.5Hz), 2.62 (td, 2H, J=2.5, 12.5 Hz), 1.89-1.72 (m, 2H, 1H), 1.23 (qd, 2H,J=4.0, 12.5 Hz). LCMS (4) Rt=1.25 min; m/z (ESI⁺) 446 (MH⁺).

Synthesis 1755-(5-(4-(methylsulfonyl)phenyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-130)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 170, steps 170-A, 170-B, 170-C, 170-D and 170-E.

¹H NMR (DMSO-d₆, 500 MHz) δ 9.15 (s, 1H), 8.74 (s, 1H), 8.00 (d, 2H,J=8.3 Hz), 7.78 (s, 1H), 7.66 (d, 2H, J=8.3 Hz), 7.11 (s, 1H), 3.26 (s,3H), 3.08 (d, 2H, J=12.2 Hz), 3.01-2.98 (m, 2H), 2.59 (t, 2H, J=11.3Hz), 1.88-1.76 (m, 2H), 1.73-1.70 (m, 2H), 1.19-1.12 (m, 1H); LC-MS (4)Rt=1.13 min; m/z (ESI⁺) 464 [MH⁺].

Synthesis 176(S)-5-(5-(4-methoxyphenyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-131)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 170, steps 170-A, 170-B, 170-C, 170-D and 170-E.

¹H NMR (MeOD-d₄, 500 MHz) δ 8.93 (s, 1H), 8.56 (s, 1H), 7.90 (d, 2H,J=8.3 Hz), 7.77 (s, 1H), 7.66 (d, 2H, J=8.3 Hz), 7.17 (s, 1H), 3.12-3.10(m, 3H), 2.76 (s, 6H), 2.63 (t, 2H, J=11.5 Hz), 1. 81 (2H, d, J=14.4Hz),1.30-1.24 (m, 2H), 0.91-0.89 (m, 2H). Rt=1.28 min; m/z (ESI⁺) 493[MH⁺].

Synthesis 1775-(5-(3-(Methylsulfonyl)phenyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-132)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 170, steps 170-A, 170-B, 170-C, 170-D and 170-E.

¹H NMR (MeOD-d₄, 500 MHz) δ 8.94 (s, 1H), 8.55 (s, 1H), 8.09-7.93 (m,2H), 7.77-7.76 (m, 3H), 7.14 (s, 1H), 3.19 (s, 3H), 3.12-3.09 (m, 4H),2.63 (dt, 2H, J,=12.6, 2.5 Hz), 1.93-1.75 (m, 3H), 1.25 (ddd, 2H, J=4.0,12.6, 16.3 Hz). LCMS (4) Rt=1.13 min; m/z (ESI⁺) 464 [MH⁺].

Synthesis 1785-(5-(4-(3-Methoxypropoxy)phenyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-133)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 171, steps 171-A, 171-B, 171-C, 171-D and 171-E.

¹H NMR (500 MHz, MeOD) δ 8.88 (s, 1H), 8.56 (s, 1H), 7.70 (s, 1H), 7.30(d, 2H, J=8.2 Hz), 7.09-7.03 (m, 2H, 1H), 4.14-4.10 (m, 2H), 3.63-3.59(m, 2H), 3.38 (s, 3H), 3.14-3.06 (s, 2H, 2H), 2.62 (t, 2H, J=12.5 Hz),2.10-2.04 (m, 2H), 1.90-1.73 (m, 2H, 1H), 1.29-1.18 (m, 2H). LCMS (4)Rt=1.47 min; m/z (ESI⁺) 474 (MH⁺).

Synthesis 1795-(5-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-134)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 171, steps 171-A, 171-B, 171-C, 171-D and 171-E.

¹H NMR (500 MHz, DMSO) δ 9.18 (s, 1H), 8.70 (s, 1H), 7.67 (s, 1H),7.00-6.92 (m, 1H, 1H), 6.85-6.79 (m, 1H, 1H), 5.68 (t, 1H, J=6.0 Hz),4.27 (s, 4H), 3.01-2.90 (m, 2H, 2H), 2.44 (t, 2H, J=11.0 Hz), 1.77-1.67(m, 1H), 1.66-1.56 (m, 2H), 1.10-1.00 (m, 2H). LCMS (4) Rt=1.34 min; m/z(ESI⁺) 444 (MH⁺).

Synthesis 1805-(5-(3-Fluorophenyl)-4-(piperidin-4-ylmethylamino)Pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-135)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 170, steps 170-A, 170-B, 170-C, 170-D and 170-E.

¹H NMR (CDCl₃, 500 MHz) δ 8.78 (s, 1H), 8.39 (s, 1H), 7.75 (s, 1H), 7.40(td, 1H, J=8.0, 6.0 Hz), 7.10 (ddd, 1H, J=7.5, 1.5, 1.0 Hz), 7.07-7.01(m, 2H), 6.92 (s, 1H), 4.56 (t, 1H, J=5.5 Hz), 3.05 (ddd, 2H, J=12.0,6.0, 3.0 Hz), 3.01 (t, 2H J=6.0 Hz), 2.53 (td, 2H, J=12.0, 2.5 Hz),1.72-1.61 (m, 4H), 1.13 (ddd, 2H, J=24.5, 12.5, 4.0 Hz). LCMS (4)Rt=1.66 min; m/z (ESI⁺) 404 (MH⁺).

Synthesis 181-A tert-Butyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate

Lithium aluminium hydride (1M in THF) (2.36 mL, 2.361 mmol) was addeddropwise to a stirred solution of 1-tert-butyl 4-ethyl4-fluoropiperidine-1,4-dicarboxylate (325 mg, 1.180 mmol) in THF (5.90mL) cooled to 0° C. After 10 min ether (15 mL) was added and thereaction was quenched by sequential dropwise addition of water (0.1 mL),10% NaOH (0.1 mL) and water (0.3 mL). The mixture was stirred at roomtemperature and the lithium salts that had precipitated were filteredoff and washed with fresh ether. The organic filtrates were combined andsolvent was removed in vacuo to leave a clear gum. The crude product wastaken up in chloroform and loaded onto a 25+M Biotage silica column.Chromatography, eluting with a gradient of EtOAc in hexanes, gavetert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (189 mg,0.810 mmol, 69%) as a clear gum.

¹H NMR (500 MHz, CDCl₃) δ 3.92 (d, 2H, J=11.0 Hz), 3.59 (d, 2H, J=20.0Hz), 3.09 (t, 2H, J=12.0 Hz), 2.17 (br s, 1H), 1.87 (m, 2H), 1.64-1.48(m, 2H), 1.45 (s, 9H).

Synthesis 181-B tert-Butyl4-fluoro-4-(tosyloxynnethyl)piperidine-1-carboxylate

p-Toluenesulfonyl chloride (230 mg, 1.209 mmol) was added portionwise totert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (188 mg,0.806 mmol), triethylamine (227 μL, 1.612 mmol), and DMAP (9.85 mg,0.081 mmol) in dichloromethane (2015 μL) at 0° C. The solution wasstirred at room temperature overnight and then partitioned betweendichloromethane and water. The organic layer was washed with 0.2M HCland then dried (MgSO₄) and concentrated. The residue was dissolved indichloromethane and loaded onto a 25+M Biotage silica column.Chromatography, eluting with a gradient of EtOAc in hexanes, gavetert-butyl 4-fluoro-4-(tosyloxymethyl)piperidine-1-carboxylate (251 mg,0.648 mmol, 80%) as a clear semi-solid.

¹H NMR (500 MHz, CDCl₃) δ 7.81 (d, 2H, J=8.0 Hz), 7.38 (d, 2H, J=8.0Hz), 4.00 (d, 2H, J=19.0 Hz), 3.95 (br s, 2H), 3.04 (t, 2H, J=12.5 Hz),2.47 (s, 3H), 1.82 (t, 2H, J=11.5 Hz), 1.63-1.47 (s, 2H), 1.46 (s, 9H).LCMS (4) Rt=2.68 min; m/z (ESI⁺) 410 (M+Na⁺).

Synthesis 181-C tert-Butyl4-((2-chloro-5-iodopyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate

Sodium hydride (60% by wt) (32.7 mg, 0.817 mmol) was added to a solutionof 2-chloro-5-iodopyridin-4-amine (160 mg, 0.629 mmol) in DMF (3930 μL)at room temperature and the mixture was stirred for 10 min. Thetemperature was raised to 80° C. and tert-butyl4-fluoro-4-(tosyloxymethyl)piperidine-1-carboxylate (244 mg, 0.629 mmol)in DMF (1 mL) was added. The reaction mixture was stirred at 80° C. for2 hr before further NaH (1.3 eq.) was added after first cooling thereaction to room temperature again. The reaction mixture was heated at120° C. for 10 hr. After cooling, the solution was partitioned betweenEtOAc (150 mL) and 1M aqueous NaHCO₃. The organic layer was washed with1M NaHCO₃ aq., sat. NaHCO₃ and brine, then dried (MgSO₄) andconcentrated. The residue was dissolved in dichloromethane/hexane andloaded onto a 25+M Biotage silica column. Chromatography, eluting with1% MeOH in dichloromethane gave partial purification. Furtherpurification by preparative thin layer chromatography, eluting with 16%EtOAc in dichloromethane, gave tert-butyl4-((2-chloro-5-iodopyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate(39 mg, 0.083 mmol, 13%) as a colourless solid.

¹H NMR (500 MHz, CDCl₃) δ 8.32 (s, 1H), 6.48 (s, 1H), 5.05 (t, 1H, J=6.0Hz), 4.02 (br s, 2H), 3.39 (dd, 2H, J=6.0, 19.5 Hz), 3.16-3.05 (m, 2H),1.99-1.91 (m, 2H), 1.70-1.53 (m, 2H), 1.48 (s, 9H). LCMS (4) Rt=2.76min; m/z (ESI⁺) 470 (MH⁺).

Synthesis 181-D tert-Butyl4-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate

MeCN (0.72 mL) and 0.5M aqueous sodium carbonate (0.24 mL, 1.5 eq.) wereadded to a mixture of tert-butyl4-((2-chloro-5-iodopyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate(37 mg, 0.079 mmol), 4-methoxyphenylboronic acid (11.97 mg, 0.079 mmol),and tetrakis(triphenylphosphine)palladium(0) (4.55 mg, 3.94 μmol) in a0.5 mL microwave reaction vial. The sealed vial was heated at 100° C.for 20 mins by microwave irradiation. The volatiles were removed invacuo. The residue was dissolved in dichloromethane and loaded onto a12+S Biotage silica column. Chromatography, eluting with a gradient ofEtOAc in hexanes, gave tert-butyl4-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate(17 mg, 0.038 mmol, 48%) as a colourless solid.

¹H NMR (500 MHz, CDCl₃) δ 7.85 (s, 1H), 7.27 (d, 2H, J=8.5 Hz), 7.03 (d,2H, J=8.5 Hz), 6.57 (s, 1H), 4.76 (t, 1H, J=6.0 Hz), 4.01 (br s, 2H),3.87 (s, 3H), 3.29 (dd, 2H, J=6.0, 20.0 Hz), 3.11-2.98 (m, 2H),1.90-1.80 (m, 2H), 1.65-1.49 (m, 2H), 1.47 (s, 9H). LCMS (4) Rt=2.78min; m/z (ESI⁺) 450 (MH⁺).

Synthesis 181-E5-(4-((4-Fluoropiperidin-4-yl)methylamino)-5-(4-methoxyphenyl)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-136)

5-Aminopyrazine-2-carbonitrile (5.45 mg, 0.045 mmol), Xantphos (1.749mg, 3.02 μmol), tris(dibenzylideneacetone)dipalladium(0) (1.384 mg,1.511 μmol), and cesium carbonate (24.62 mg, 0.076 mmol) were added totert-butyl44(2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate(17 mg, 0.038 mmol) in a 0.2 mL microwave reaction vial. The vial wassealed and an inert atmosphere was introduced before dry dioxane (291μL) was added. Nitrogen was bubbled through the mixture for 5 min. Themixture was heated at 150° C. for 1 hr by microwave irradiation. Aftercooling the mixture was diluted with 20% dichloromethane in MeOH andloaed onto a preparative thin layer chromatography plate. Elution with50% EtOAc in hexane gave tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate(1.5 mg, 2.81 μmol, 7% yield) as a light yellow powder. LCMS (4) Rt=2.35min; m/z (ESI⁺) 534 (MH⁺). Trifluoroacetic acid (0.1 mL, 1.298 mmol) wasadded to tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate(1.5 mg, 2.81 μmol) dissolved in dichloromethane (0.5 mL) and thesolution was stirred for 1 hr. The volatiles were removed in vacuo andthe crude product was purified by ion exchange on (solute SCX II acidicresin (1 g), followed by preparative thin layer chromatography, elutingwith 10% MeOH/1% NH₃/89% dichloromethane, to give5-(4-((4-fluoropiperidin-4-yl)methylamino)-5-(4-methoxyphenyl)pyridin-2-ylamino)pyrazine-2-carbonitrile(1 mg, 2.307 μmol, 82% yield) as a yellow powder.

¹H NMR (500 MHz, MeOD) δ 8.87 (s, 1H), 8.59 (s, 1H), 7.75 (s, 1H), 7.33(d, 2H, J=8.5 Hz), 7.21 (s, 1H), 7.07 (d, 2H, J=8.5 Hz), 3.86 (s, 3H),3.44 (d, 2H, J=19.5 Hz), 3.08-2.93 (m, 4H), 1.96-1.69 (m, 4H). LCMS (4)Rt=1.62 min; m/z (ESI⁺) 434 (MH⁺).

Synthesis 1825-(5-(4-methoxyphenyl)-4-(2-(morpholin-2-yl)ethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-137)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 171, steps 171-A, 171-B, 171-C, 171-D and 171-E.

¹H NMR (MeOD-d₄, 500 MHz,) δ 8.85 (s, 1H), 8.54 (s, 1H), 7.69 (s, 1H),7.30 (d, 2H, J=11.4 Hz), 7.05 (d, 2H, J=11.5 Hz), 6.99 (s, 1H), 3.85 (s,3H), 3.73-3.70 (m, 1H), 3.61-3.51 (m, 2H), 3.35-3.26 (m, 2H), 2.99-2.79(m, 2H), 2.63 (dd, 1H, J=10.8, 12.5 Hz), 1.82-1.67 (m, 2H). LCMS (4)Rt=1.64 min; m/z (ESI⁺) 432 [MH⁺].

Synthesis 1835-(4-(2-(Morpholin-2-yl)ethylamino)-5-phenylpyridin-2-ylamino)pyrazine-2-carbonitrile(Y-138)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 171, steps 171-A, 171-B, 171-C, 171-D and 171-E.

¹H NMR (CDCl₃, 500 MHz) δ 8.88 (s, 1H), 8.54 (s, 1H), 7.71 (s, 1H),7.50-7.47 (m, 3H), 7.00 (s, 1H), 3.62-3.52 (m, 2H), 3.48-3.43 (m, 1H),3.29-3.23 (m, 2H), 2.85-2.70 (m, 3H), 2.53 (dd, 2H, J=12.5, 10.6 Hz),1.82-1.62 (m, 2H). LCMS (4) Rt=1.35 min; m/z (ESI⁺) 402 [MH⁺].

Synthesis 184-A (E)-tert-Butyl4-((2-chloro-5-(3-methoxyprop-1-enyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

A solution of tert-butyl4-((2-chloro-5-iodopyridin-4-ylamino)methyl)piperidine-1-carboxylate(Synthesis 170-B) (0.100 g, 0.22 mmol),(E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.044 g, 0.22 mmol), sodium carbonate (0.5 M, 0.66 mL) andtetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.01 mmol) inacetonitrile (2.00 mL) was heated under microwave irradiation for 20 minat 100° C. The solvent was removed in vacuo and the crude product waspurified by silica column chromatography, eluting with ethyl acetate andhexane (1/1). to give the title compound as a colourless oil (0.057 g,65%).

¹H NMR (CDCl₃, 500 MHz) δ 7.90 (s, 1H), 6.42 (s, 1H), 6.42-6.38 (s, 1H),6.11 (dt, 1H, J=5.3, 15.7 Hz), 4.64 (t, 1H, J=5.7 Hz), 4.13 (s, 2H),4.06 (d, 2H, J=6.9 Hz), 3.40 (s, 3H), 3.05 (t, 2H, J=6.2 Hz), 2.69 (s,2H), 1.78-1.71 (m, 3H), 1.44 (s, 9H), 1.18-1.12 (m, 4H). LCMS (4)Rt=2.59 min; m/z (ESI⁺) 396 [MH⁺].

Synthesis 184-B (E)-tert-butyl44(2-(5-cyanopyrazin-2-ylamino)-5-(3-methoxyprop-1-enyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

A solution of (E)-tert-butyl4-((2-chloro-5-(3-methoxyprop-1-enyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(0.040 g, 0.101 mmol), 2-amino-4-cyanopyrazine (0.018 g, 0.152 mmol),Xantphos (0.009 g, 0.016 mmol), cesium carbonate (0.065 g, 0.20 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (0.007 g, 0.008mmol) in dioxane (0.7 mL) was stirred at room temperature under nitrogenfor 10 min, then heated under microwave irradiation for 60 min at 150°C. The reaction mixture was purified by ion exchange on SCX-II acidicresin (1 g), eluting with methanol/DCM (1/1) then 2M ammonia-methanol.The basic fractions were combined and the solvent was removed in vacuo.The crude product was purified by preparative thin layer chromatography,eluting with ethyl acetate/hexane (1/1), to give the title compound as ayellow solid (0.020 g, 41%).

¹H NMR (CDCl₃, 500 MHz) δ 8.73 (s, 1H), 8.44 (s, 1H), 7.92 (s, 1H), 7.06(s, 1H), 6.46 (d, 1H, J=15.7 Hz), 6.15 (dt, 1H, J=5.3, 15.6 Hz), 4.63(t, 1H, J=5.4 Hz), 4.23-4.11 (m, 5H), 3.45 (s, 3H), 3.16 (t, 2H, J=6.1Hz), 2.73 (t, 2H, J=11.5 Hz), 1.92-1.73 (m, 3H), 1.48 (s, 9H), 1.36-1.18(m, 4H). LCMS (4) Rt=2.14 min; m/z (ESI⁺) 480 [MH⁺].

Synthesis 184-C(E)-5-(5-(3-Methoxyprop-1-enyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-139)

TFA (0.2 mL) was added at room temperature to a solution of(E)-tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-methoxyprop-1-enyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(0.020 g, 0.041 mmol) in dichloromethane (2 mL). The reaction mixturewas stirred for 20 min. Solvent was removed in vacuo and the mixture waspurified by ion exchange on SCX-II acidic resin (500 mg) eluting withmethanol, then 2M ammonia-methanol. The basic fractions were combinedand the solvent was removed in vacuo. The crude product was purified bypreparative thin layer chromatography, eluting withmethanol/dichloromethane/NH₃ (9%/90%/1%) to give the title compound as ayellow solid (0.008 g, 51%).

¹H NMR (MeOD-d₄, 500 MHz) δ 8.83 (s, 1H), 8.53 (s, 1H), 7.93 (s, 1H),7.01 (s, 1H), 6.75-6.55 (m, 1H), 6.14 (dt, 1H, J=6.0, 15.6 Hz), 4.11(dd, 2H, J=1.2, 6.0 Hz), 3.41 (s, 3H), 3.19-3.09 (m, 4H), 2.66 (td, 2H,J=2.3, 12.4 Hz), 1.96-1.78 (m, 3H), 1.36-1.22 (m, 2H). LCMS (4) Rt=1.20min; m/z (ESI⁺) 380 [MH⁺].

Synthesis 185(E)-5-(5-(4-Hydroxybut-1-enyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-140)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 184, steps 184-A, 184-B and 184-C.

¹H NMR (500 MHz, MeOD) δ 8.80 (s, 1H), 8.55 (s, 1H), 7.90 (s, 1H), 7.01(s, 1H), 6.44 (d, 1H, J=15.5 Hz), 6.08 (dt, 1H, J=6.5, 15.5 Hz), 3.71(t, 2H, J=6.5 Hz), 3.27 (s, 2H), 3.18 (d, 2H, J=6.5 Hz), 2.81 (td, 2H,J=2.0, 12.5 Hz), 2.48 (td, 2H, J=1.0, 7.5 Hz), 2.02-1.91 (m, 2H, 1H),1.44-1.34 (m, 2H). LCMS (4) Rt=1.14 min; m/z (ESI⁺) 380 (MH⁺).

Synthesis 1865-(5-(3-methoxypropyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-141)

A solution of (E)-tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-methoxyprop-1-enyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(Synthesis 183-B) (0.035 g, 0.073 mmol), palladium on carbon (0.035 g)in methanol (2 mL) was stirred overnight under hydrogen (1 atm). Thereaction mixture was filtered through celite and the solvent was removedin vacuo. The crude oproduct was used without further purification. TFA(0.2 mL) was added to a solution of the crude material dissolved indichloromethane (2 mL) at room temperature. The reaction mixture wasstirred for 20 min. Solvent was removed in vacuo and the mixture waspurified by ion exchange on SCX-II acidic resin (500 mg) eluting withmethanol, then 2M ammonia-methanol. The basic fractions were combinedand the solvent was removed in vacuo. The crude product was purified bypreparative thin layer chromatography, eluting withmethanol/dichloromethan/NH₃ (9%/90%/1%), to give the title compound as ayellow solid (0.020 g, 84%).

¹H NMR (MeOD-d₄, 500 MHz,) δ 8.74 (s, 1H), 8.50 (s, 1H), 7.68 (s, 1H),6.91 (s, 1H), 3.46 (t, 1H, J=6.5 Hz), 3.38 (s, 3H), 3.16-3.14 (m, 4H),2.69 (dd, 2H, J=10.1, 12.5 Hz), 2.56 (t, 2H, 7.5 Hz), 2.00-1.75 (m, 5H),1.41-1.22 (m, 2H). LCMS (4) Rt=1.20 min; m/z (ESI⁺) 382 [MH⁺].

Synthesis 1875-(5-(4-hydroxybutyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-142)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 184 and Synthesis 186.

¹H NMR (500 MHz, MeOD) δ 8.68 (s, 1H), 8.56 (s, 1H), 7.74 (s, 1H), 6.67(s, 1H), 3.65 (t, 2H, J=6.0 Hz), 3.49-3.44 (s, 2H), 3.36-3.32 (m, 2H),3.02 (td, 2H, J=3.0, 13.0), 2.60 (t, 2H, J=7.5 Hz), 2.19-2.02 (m, 2H,1H), 1.74-1.62 (m, 2H+2H), 1.60-1.49 (m, 2H). LCMS (4) Rt=1.12 min; m/z(ESI⁺) 382 (MH⁺).

Synthesis 1885-(5-(3-hydroxypropyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-143)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 184 and Synthesis 186.

¹H NMR (500 MHz, MeOD) δ 8.73 (s, 1H), 8.51 (d, 1H, J=1.5 Hz), 7.70 (s,1H), 6.92 (s, 1H), 3.63 (t, 2H, J=6.0 Hz), 3.18-3.11 (m, 4H), 2.66 (td,2H, J=2.5, 12.5 Hz), 2.59-2.54 (m, 2H), 1.96-1.75 (m, 1H, 2H, 2H),1.35-1.24 (m, 2H).

Synthesis 189-A tert-Butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

A solution of tert-butyl4-((2-chloro-5-iodopyridin-4-ylamino)methyl)piperidine-1-carboxylate(Synthesis 170-B) (0.100 g, 0.22 mmol),dichlorobis(triphenylphosphine)-palladium(II) (0.009 g, 0.01 mmol),trimethyl(2-methylbut-3-yn-2-yloxy)silane (0.048 mL, 0.24 mmol) andcopper iodide (0.002 g, 0.01 mmol) was heated under microwaveirradiation for 5 min at 120° C. The crude mixture was concentrated invacuo and filtered through a pad of silica, eluting with hexane/ethylacetate (8/2), to give the crude product which was used without furtherpurification. The crude pyridine (0.085 g, 0.163 mmol),2-amino-4-cyanopyrazine (0.023 g, 0.195 mmol), Xantphos (0.015 g, 0.026mmol), cesium carbonate (0.106 g, 0.326 mmol),dichlorobis(triphenylphosphine)-palladium(II) (0.012 g, 0.013 mmol) indioxane (1.2 mL) were stirred at room temperature under nitrogen for 10min, then heated under microwave irradiation for 60 min at 150° C. Thereaction mixture was purified by ion exchange on SCX-II acidic resin (2g), eluting with methanol/dichloromethane (1/1), then 2Mammonia-methanol. The basic fractions were combined and solvent wasremoved in vacuo. The crude product was purified by preparative thinlayer chromatography, eluting with methanol/dichloromethane (1/19), togive the title compound as a yellow solid (0.024 g, 27%).

¹H NMR (CDCl₃, 500 MHz) δ 8.62 (s, 1H), 8.44 (s, 1H), 8.00 (s, 1H), 7.17(s, 1H), 5.19 (t, 1H, J=5.8 Hz) 4.19-4.16 (m, 2H), 3.17 (t, 2H, J=6.1Hz), 2.72 (t, 2H, J=11.3 Hz), 1.84-1.75 (m, 3H), 1.66 (s, 6H), 1.47 (s,9H), 1.27-1.21 (m, 2H), 0.90-0.84 (m, 1H). LCMS (4) Rt=2.17 min; m/z(ESI⁺) 492 [MH⁺].

Synthesis 189-B5-(5-(3-Hydroxy-3-methylbut-1-ynyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-144)

TFA (0.2 mL) was added at room temperature to a solution of tert-butyl4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate(0.020 g, 0.041 mmol) dissolved in dichloromethane (2 mL). The reactionmixture was stirred for 20 min. Solvent was removed in vacuo and thecrude mixture was purified by ion exchange on SCX-II acidic resin (500mg), eluting with methanol then 2M ammonia-methanol. The basic fractionswere combined and solvent was removed in vacuo. The crude product waspurified by preparative thin layer chromatography, eluting withmethanol/dichloromethane (1/19), to give the title compound as a yellowsolid (0.008 g, 50%).

¹H NMR (MeOD-d₄, 500 MHz) δ 8.89 (s, 1H), 8.55 (s, 1H), 7.93 (s, 1H),7.06 (s, 1H), 3.36 (s, 1H), 3.18 (d, 2H, J=6.4 Hz), 3.10 (d, 2H, J=12.4Hz),2.62 (dt, 2H, J=12.4, 2.2 Hz), 1.87-1.89 (m, 2H), 1.60 (s, 6H),1.32-1.26 (m, 2H). LC-MS (4) Rt=1.85 min; m/z (ESI⁺) 392 [MH⁺].

Synthesis 1905-(5-(3-Hydroxyprop-1-ynyl)-4-(piperidin-4-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-145)

The title compound was prepared using methods analogous to thosedescribed in Synthesis 189, steps 189-A and 189-B.

¹H NMR (500 MHz, DMSO) δ 9.09 (s, 1H), 8.73 (s, 1H), 7.96 (s, 1H), 7.02(s, 1H), 6.23 (t, 1H, J=6.0 Hz), 5.28 (br s, 1H), 4.35 (s, 2H), 3.07 (t,2H, J=6.5 Hz), 3.00-2.95 (m, 2H), 2.49-2.41 (m, 2H), 1.77-1.67 (m, 1H),1.67-1.61 (m, 2H), 1.16-1.06 (m, 2H). LCMS (4) Rt=1.02 min; m/z (ESI⁺)364 (MH⁺).

Synthesis 191-A (S)-2-Chloro-N-(2,3-dihydroxypropyl)acetamide

Triethylamine (4.0 ml, 28.9 mmol) was added to a solution of(S)-3-amino-1,2-propanediol (2.2 g, 24.1 mmol) in a mixture ofCH₃CN/MeOH (80 mL/13 mL) at −10° C. under nitrogen. Chloroacetylchloride (2.1 mL, 26.5 mmol) was then added dropwise at −10° C. over 30min. The reaction mixture was allowed to reach room temperature andstirred for 16 h. The mixture was concentrated under vacuum and purifiedby flash column chromatography on silica gel, eluting withmethanol/ethyl acetate (8/92), to give the title compound as a whitesolid (3.63 g, 90%).

¹H NMR (DMSO-d₆, 500 MHz,) δ 9.10 (s, 1H), 4.79 (d, 1H, J=5.0 Hz), 4.53(t, 1H, J=5.6 Hz), 4.07 (s, 1H), 3.53-3.47 (m, 2H), 3.33-3.23 (m, 3H),3.02-2.97 (m, 1H).

Synthesis 191-B (S)-6-(Hydroxymethyl)morpholin-3-one

(S)-2-Chloro-N-(2,3-dihydroxypropyl)acetamide (4.77 g, 28.45 mmol) intert-amyl alcohol (75 mL) was added over 2 h to a stirred solution ofpotassium tert-butoxide (3.59 g, 21.4 mmol) in tert-amyl alcohol (25 mL)at room temperature under nitrogen. After 1 hr, methanol (12 mL) andwater (0.7 mL) were added and the reaction mixture was stirred for anadditional 20 min. The mixture was concentrated under vacuum andpurified by flash column chromatography on silica gel, eluting withmethanol/ethyl acetate (2/8), to give the title compound as a whitesolid (1.26 g, 45%).

¹H NMR (DMSO-d₆, 500 MHz) δ 7.90 (s, 1H), 4.83 (t, 1H, J=5.7 Hz), 4.04(AB, 2H, J=16.4 Hz), 3.66-3.62 (m, 1H), 3.50-3.38 (m, 2H), 3.19-3.15 (m,1H), 3.09-3.05 (m, 1H).

Synthesis 191-C (S)-Morpholin-2-ylmethanol

A solution of Red-Al (bis(2-methoxyethoxy)aluminum hydride) (65 wt. % intoluene, 0.46 mL, 1.52 mmol) was slowly added over 1 h to a suspensionof (S)-6-(hydroxymethyl)morpholin-3-one (0.050 g, 0.38 mmol) inanhydrous THF (2 mL) at 0° C. under nitrogen. The reaction mixture wasstirred for 16 h room temperature and then cooled to 0° C. before theaddition of water (0.5 mL) followed by 4M potassium hydroxide (1 mL).The resulting precipitate was filtered through celite and rinsed withdichloromethane. The filtrate was concentrated under vacuum and purifiedby flash column chromatography on silica gel, eluting withmethanol/chloroform (25/75), to give the title compound as a pale yellowoil (0.015 g, 33%).

¹H NMR (Acetone-d₆, 500 MHz,) δ 3.73 (dt, 1H, J=10.7, 2.5 Hz), 3.51-3.38(m, 4H), 3.16 (s, 1H), 2.90-2.87 (m, 1H), 2.72-2.70 (m, 2H), 2.50-2.45(m, 1H).

Synthesis 191-D (S)-tert-Butyl 2-(hydroxymethyl)morpholine-4-carboxylate

Di-tert-butyl dicarbonate (0.606 g, 2.77 mmol was added to a solution of(S)-morpholin-2-ylmethanol (0.316 g, 2.69 mmol) and triethylamine (0.54mL, 3.71 mmol) in dichloromethane (12 mL). The reaction mixture wasstirred for 16 h at room temperature. The organic solution was washedwith 2M HCl (12 mL), and the aqueous phase was extracted withdichloromethane (2×10 mL). The combined organic phases were dried(MgSO₄) and the solvent was removed in vacuo. The crude product waspurified by flash column chromatography on silica gel, eluting withethyl acetate/hexane (1/1), to give the title compound as a colourlessoil (0.500 g, 85%).

¹H NMR (CDCl₃, 500 MHz) δ 3.91-3.86 (m, 3H), 3.68-3.65 (m, 1H),3.59-3.49 (m, 3H), 2.95-2.93 (m, 1H), 2.77-2.75 (m, 2H), 2.10 (s, 1H),1.46 (s, 9H).

Synthesis 191-E (S)-tert-Butyl2-(tosyloxymethyl)morpholine-4-carboxylate

Toluene suiphonyl chloride (0.513 g, 2.69 mmol) was added to a solutionof (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (0.390 g,1.79 mmol), triethylamine (0.50 mL, 3.59 mmol) and DMAP (cat.) indichloromethane (11 mL). The reaction mixture was stirred for 24 h thendiluted with dichloromethane (25 ml) and washed sequentially with water(25 mL) and 0.2M HCl (25 mL). The organic phase was dried (Na₂SO₄) andthe solvent was removed in vacuo. The crude product was purified byflash column chromatography on silica gel, eluting with ethylacetate/hexane (1/5), to give the title compound as a colourless solid(0.650 g, 97%).

¹H NMR (CDCl₃, 500 MHz,) δ 7.76 (d, 2H, J=8.5 Hz), 7.31 (d, 2H, J=8.5Hz), 4.00-3.96 (m, 2H), 3.89-3.76 (m, 3H), 3.62-3.58 (m, 1H), 3.48-3.43(m, 1H), 2.91-2.87 (m, 1H), 2.69-2.65 (m, 1H), 2.45 (s, 3H), 1.41 (s,9H). LCMS (4) Rt=2.53 min; m/z (ESI⁺) 394 [M+Na⁺].

Synthesis 191-F (R)-tert-Butyl2-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate

NaH (0.024 g, 0.569 mmol) was added to a solution of2-chloro-5-iodopyridin-4-amine (0.121 g, 0.474 mmol) in DMF (2.8 mL) atroom temperature and stirred for 10 min. The temperature was raised to80° C. and (R)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate(0.264 g, 0.711 mmol) in DMF (0.6 mL) was added. The reaction mixturewas stirred for 2 h before further NaH (0.024 g, 0.569 mmol) was addedat room temperature. The reaction mixture was heated at 80° C. for afurther 1 h then cooled. Water was added and the mixture was partitionedbetween ethyl acetate (20 mL) and aq. NaHCO₃ (20 mL). The organic phasewas washed with brine, dried (MgSO₄) and concentrated. The mixture waspurified by flash column chromatography on silica gel, eluting withethyl acetate and hexane (2/4), to give an an inseparable mixture ofstarting material and product. LC-MS (4) Rt=2.66 min; m/z (ESI⁺) 397[MH⁺]. A solution of the crude (R)-tert-butyl2-((2-chloro-5-iodopyridin-4-ylamino)methyl)morpholine-4-carboxylate(0.040 g, 0.088 mmol), sodium carbonate (0.5 M, 0.26 mL),4-methoxyphenyl boronic acid (0.013 g, 0.088 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.01 mmol) inacetonitrile (2 mL) was heated under microwave irradiation at 100° C.for 20 min. The reaction mixture was concentrated in vacuo. The mixturewas purified by flash column chromatography on silica gel, eluting withethyl acetate/hexane (1/1), to give the title compound as colorless oil(0.036 g, 94%).

¹H NMR (CDCl₃, 500 MHz) δ 7.83 (s, 1H), 7.27 (d, 1H, J=11.6 Hz), 7.01(d, 1H, J=11.6 Hz), 6.53 (s, 1H), 4.85 (t, 1H, J=5.3 Hz), 3.89-3.82 (m,5H), 3.56-3.50 (m, 1H), 3.48 (dd, 1H, J=2.4, 11.4 Hz), 3.27-3.11 (m,2H), 2.96-2.83 (m, 1H), 2.75-2.61 (m, 1H), 2.40 (s, 1H), 1.46 (s, 9H).LCMS (4) Rt=2.66 min; m/z (ESI⁺) 434 [MH⁺].

Synthesis 191-G (R)-tert-Butyl2-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate

A solution of (R)-tert-butyl2-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate(0.036 g, 0.083 mmol), 2-amino-4-cyanopyrazine (0.014 g, 0.116 mmol),Xantphos (0.008 g, 0.013 mmol), cesium carbonate (0.054 g, 0.166 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (0.007 g, 0.008mmol) in dioxane (0.7 mL) was stirred at room temperature under nitrogenfor 10 min, then heated under microwave irradiation for 60 min at 150°C. The reaction mixture was purified by ion exchange on SCX-II acidicresin (1 g), eluting with methanol/dichloromethane (1/1) then 2Mammonia-methanol. The basic fractions were combined and solvent wasremoved in vacuo. The crude product was purified by preparative thinlayer chromatography, eluting with ethyl acetate/hexane (1/1), to givethe title compound as a yellow solid (0.014 g, 32%).

¹H NMR (CDCl₃, 500 MHz) δ 8.82 (s, 1H), 8.46 (s, 1H), 7.79 (s, 1H), 7.31(d, 2H, J=8.7 Hz), 7.06 (s, 1H), 7.03 (d, 2H, J=8.7 Hz), 5.01 (t, 1H,J=5.3 Hz), 3.85 (s, 3H), 3.86-3.84 (m, 1H), 3.74-3.64 (m, 1H), 3.30-3.50(m, 1H), 3.26-3.17 (m, 2H), 2.99 (d, 1H, J=13.7 Hz), 2. 86 (2H, d, J=6.9Hz), 2.73-2.63 (m, 1H). LCMS (4) Rt=2.17 min; m/z (ESI⁺) 518 [MH⁺].

Synthesis 191-H(S)-5-(5-(4-Methoxyphenyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-146)

TFA (0.2 mL) was added to a solution of (R)-tert-butyl2-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate(0.014 g, 0.027 mmol) dissolved in dichloromethane (2 mL) at roomtemperature. The reaction mixture was stirred for 20 min. Solvent wasremoved in vacuo and the mixture was purified by ion exchange on SCX-IIacidic resin (500 mg), eluting with methanol then 2M ammonia-methanol.The basic fractions were combined and solvent was removed in vacuo. Thecrude product was purified by preparative thin layer chromatography,eluting with methanol/dichloromethane (1/19), to give the title compoundas a yellow solid (0.007 g, 62%).

¹H NMR (CDCl₃, 500 MHz) δ 8.78 (s, 1H), 8.46 (s, 1H), 7.79 (s, 1H), 7.31(d, 2H, J=8.7 Hz), 7.06 (s, 1H), 7.03 (d, 2H, J=8.7 Hz), 5.01 (t, 1H,J=5.3 Hz), 3.85 (s, 3H), 3.86-3.84 (m, 1H), 3.74-3.64 (m, 1H), 3.30-3.50(m, 1H), 3.26-3.17 (m, 2H), 2.99 (d, 1H, J=13.7 Hz), 2.86 (2H, d, J=6.9Hz), 2.73-2.63 (m, 1H). LCMS Rt=1.33 min; m/z (ESI⁺) 418 [MH ⁺].

Synthesis 192-A (R)-2-Chloro-N-(2,3-dihydroxypropyl)acetamide

Triethylamine (1.83 mL, 13.2 mmol) was added to a solution of(R)-3-amino-1,2-propanediol (1.00 g, 11.0 mmol) in a mixture CH₃CN/MeOH(36 mL/16 mL) at −10° C. under nitrogen. Chloroacetyl chloride (0.98 ml,12.0 mmol) was added dropwise at −10° C. over 30 min. The reactionmixture was allowed to reach room temperature and stirred for 16 h. Themixture was concentrated and purified by flash column chromatography onsilica gel, eluting with methanol/ethyl acetate (8/92), to give thetitle compound as a white solid (1.43 g, 78%).

¹H NMR (Acetone-d₆, 500 MHz,) δ 7.59 (s, 1H), 4.12 (s, 2H), 4.08 (brs,1H), 3.84 (s, 1H), 3.73 (q, 1H, J=5.4 Hz), 3.50 (q, 1H, J=5.4 Hz),3.47-3.42 (m, 1H), 3.32-3.27 (m, 1H).

Synthesis 192-B (R)-6-(Hydroxymethyl)morpholin-3-one

(R)-2-Chloro-N-(2,3-dihydroxypropyl)acetamide (1.31 g, 8.20 mmol) intert-amyl alcohol (34 mL) was added dropwise over 2 h to a stirredsolution of potassium tert-butoxide (2.30 g, 20.6 mmol) in tert-amylalcohol (16 mL) at room temperature under nitrogen. After 1 hr, MeOH (8mL) and water (0.5 mL) were added and the reaction mixture was stirredfor an additional 20 min. The mixture was concentrated under vacuum andpurified by flash column chromatography on silica gel, eluting withmethanol/ethyl acetate (2/8) to give the title compound as a white solid(0.59 g, 54%).

¹H NMR (DMSO-d₆, 500 MHz) δ 7.90 (s, 1H), 4.83 (t, 1H, J=5.7 Hz), 4.04(AB, 2H, J=16.4 Hz), 3.66-3.62 (m, 1H), 3.50-3.38 (m, 2H), 3.19-3.15 (m,1H), 3.09-3.05 (m, 1H).

Synthesis 192-C (R)-Morpholin-2-ylmethanol

A solution of Red-Al (bis(2-methoxyethoxy)aluminum hydride) (65 wt. % intoluene, 0.93 mL, 3.04 mmol) was slowly added over 1 h to a suspensionof (S)-6-(hydroxymethyl)morpholin-3-one (0.100 g, 0.76 mmol) inanhydrous THF (4 mL) at 0° C. under nitrogen. The reaction mixture wasstirred for 16 h at room temperature, then cooled to 0° C. before theaddition of water (1 mL) followed by 4M potassium hydroxide (2 mL). Theresulting precipitate was filtered through celite and rinsed withdichloromethane. The organic filtrate was concentrated under vacuum andpurified by flash column chromatography on silica gel, eluting withmethanol/chloroform (25/75), to give the title compound as a pale yellowoil (0.040 g, 44%).

¹H NMR (Acetone-d₆, 500 MHz,) δ 3.73 (dt, 1H, J=10.7, 2.5 Hz), 3.51-3.38(m, 4H), 3.16 (s, 1H), 2.90-2.87 (m, 1H), 2.72-2.70 (m, 2H), 2.50-2.45(m, 1H).

Synthesis 192-D (R)-tert-Butyl 2-(hydroxymethyl)morpholine-4-carboxylate

Di-tert-butyl dicarbonate (0.558 g, 2.55 mmol) was added to a solutionof (R)-morpholin-2-ylmethanol (0.291 g, 2.48 mmol) and triethylamine(0.47 mL, 3.42 mmol) in dichloromethane (11 mL). The reaction mixturewas stirred for 16 h at room temperature. The organic solution waswashed with 2M HCl (10 mL), and the aqueous phase was extracted withdichloromethane (2×10 mL). The combined organic extracts were dried(MgSO₄) and solvent was removed in vacuo. The crude product was purifiedby flash column chromatography on silica gel, eluting with ethylacetate/hexane (1/1). to give the title compound as a colourless oil(0.360 g, 64%).

¹H NMR (CDCl₃, 500 MHz) δ 3.91-3.86 (m, 3H), 3.68-3.65 (m, 1H),3.59-3.49 (m, 3H), 2.95-2.93 (m, 1H), 2.77-2.75 (m, 2H), 2.10 (s, 1H),1.46 (s, 9H).

Synthesis 192-E (R)-tert-Butyl2-(tosyloxymethyl)morpholine-4-carboxylate

Toluene sulphonyl chloride (0.473, 2.48 mmol) was added to a solution of(R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (0.360, 1.65mmol), triethylamine (0.45 mL, 3.30 mmol) and DMAP (cat.) indichloromethane (10 mL). The reaction mixture was stirred for 24 h thendiluted with dichloromethane (20 mL) and washed sequentially with water(20 mL) and 0.2M HCl (20 mL). The organic phase was dried (Na₂SO₄) andsolvent was removed in vacuo. The crude product was purified by flashcolumn chromatography on silica gel, eluting with ethyl acetate/hexane(1/5), to give the title compound as a colourless solid (0.542 g, 88%).

¹H NMR (CDCl₃, 500 MHz,) δ 7.81 (d, 2H, J=8.5 Hz), 7.35 (d, 2H, J=8.5Hz), 4.06-3.89 (m, 2H), 3.89-3.81 (m, 3H), 3.62-3.58 (m, 1H), 3.48-3.43(m, 1H), 2.91-2.87 (m, 1H), 2.69-2.65 (m, 1H), 2.45 (s, 3H), 1.46 (s,9H). LC-MS (4) Rt=2.53 min; m/z (ESI⁺) 394 [M+Na⁺].

Synthesis 192-F (S)-tert-Butyl2-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate

NaH (0.024 g, 0.569 mmol) was added to a solution of2-chloro-5-iodopyridin-4-amine (0.121 g, 0.474 mmol) in DMF (2.8 mL) atroom temperature and stirred for 10 min. The temperature was raised to80° C. and (S)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate(0.264 g, 0.711 mmol) in DMF (0.6 mL) was added. The reaction mixturewas stirred for 2 h, then further NaH (0.024 g, 0.569 mmol) was added atroom temperature. The reaction mixture was further heated at 80° C. for1 h then cooled. Water was added and the mixture was partitioned betweenethyl acetate (20 mL) and aq. NaHCO₃ (20 mL). The organic phase waswashed with brine, dried (MgSO₄) and concentrated. The mixture waspurified by flash column chromatography on silica gel, eluting withethyl acetate/hexane (2/4), to give an inseparable mixture of startingmaterial and product. LCMS (4) Rt=2.66 min; m/z (ESI⁺) 397 [MH⁺]. Asolution of the crude (R)-tert-butyl2-((2-chloro-5-iodopyridin-4-ylamino)methyl)morpholine-4-carboxylate(0.040 g, 0.088 mmol), sodium carbonate (0.5 M, 0.26 mL),4-methoxyphenyl boronic acid (0.013 g, 0.088 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.01 mmol) inacetonitrile (2 mL) was heated under microwave irradiation at 100° C.for 20 min. The reaction mixture was concentrated. The crude product waspurified by flash column chromatography on silica gel, eluting withethyl acetate/hexane (1/1), to give the title compound as a colorlessoil (0.036 g, 94%).

¹H NMR (CDCl₃, 500 MHz) δ 7.82 (s, 1H), 7.27 (d, 1H, J=11.6 Hz), 7.01(d, 1H, J=11.6 Hz), 6.53 (s, 1H), 4.86 (t, 1H, J=5.3 Hz), 3.89-3.82 (m,5H), 3.56-3.50 (m, 1H), 3.48 (dd, 1H, J=2.4, 11.4 Hz), 3.27-3.11 (m,2H), 2.96-2.83 (m, 1H), 2.75-2.61 (m, 1H), 2.40 (s, 1H), 1.46 (s, 9H).LCMS (4) Rt=2.66 min; m/z (ESI⁺) 434 [MH⁺].

Synthesis 192-G (S)-tert-Butyl2-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate

A solution of (S)-tert-butyl2-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate(0.036 g, 0.083 mmol), 2-amino-4-cyanopyrazine (0.014 g, 0.116 mmol),Xantphos (0.008 g, 0.013 mmol), cesium carbonate (0.054 g, 0.166 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (0.007 g, 0.008mmol) in dioxane (0.7 mL) was stirred at room temperature under nitrogenfor 10 min then heated under microwave irradiation for 60 min at 150° C.The reaction mixture was purified by ion exchange on SCX-II acidic resin(1 g), eluting with methanol/dichloromethane (1/1), then 2Mammonia-methanol. The basic fractions were combined and the solvent wasremoved in vacuo. The crude product was purified by preparative thinlayer chromatography, eluting with ethyl acetate/hexane (1/1), to givethe title compound as a yellow solid (0.014 g, 32%).

¹H NMR (CDCl₃, 500 MHz) δ 8.81 (s, 1H), 8.51 (s, 1H), 7.79 (s, 1H), 7.30(d, 2H, J=8.5 Hz), 7.06 (s, 1H), 7.02 (d, 2H, J=8.5 Hz), 4.95 (t, 1H,J=5.2 Hz), 3.87 (s, 3H), 3.88-3.84 (m, 1H), 3.65-3.60 (m, 1H), 3.52-3.48(m, 2H), 3.33-3.20 (m, 2H), 2.97-2.90 (m, 1H), 2.76-2.67 (m, 1H), 1.47(s, 9H). LCMS (4) Rt=2.17 min; m/z (ESI⁺) 518 [MH⁺].

Synthesis 192-H(R)-5-(5-(4-Methoxyphenyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-147)

TFA (0.1 mL) was added to a solution of tert-butyl (S)-tert-butyl2-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate(0.006 g, 0.012 mmol) dissolved in dichloromethane (1 mL) at roomtemperature. The reaction mixture was stirred for 20 min. Solvent wasremoved in vacuo and the mixture was purified by ion exchange on SCX-IIacidic resin (500 mg), eluting with methanol then 2M ammonia-methanol.The basic fractions were combined and solvent was removed in vacuo. Thecrude product was purified by preparative thin layer chromatography,eluting with methanol/dichloromethane (1/19), to give the title compoundas a yellow solid (0.003 g, 62%).

¹H NMR (CDCl₃, 500 MHz) δ 8.82 (s, 1H), 8.46 (s, 1H), 7.79 (s, 1H), 7.31(d, 2H, J=8.7 Hz), 7.06 (s, 1H), 7.03 (d, 2H, J=8.7 Hz), 5.11 (t, 1H,J=5.3 Hz), 3.85 (s, 3H), 3.86-3.84 (m, 1H), 3.74-3.71 (m, 1H), 3.65-3.62(m, 1H), 3.30-3.24 (m, 2H), 2.99 (d, 1H, J=13.7 Hz), 2.86 (d, 2H, J=6.9Hz), 2.73-2.66 (m, 1H). LCMS Rt=1.33 min; m/z (ESI⁺) 418 [MH⁺].

Synthesis 193(S)-5-(5-(4-(Methoxymethyl)phenyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-148)

Prepared using methods analogous to those in Synthesis 191, steps 191-F,191-G and 191-H.

¹H NMR (MeOD-d₄, 500 MHz) δ 8.92 (d, 1H, J=0.9 Hz), 8.57 (d, 1H, J=1.4Hz), 7.77 (s, 1H), 7.48 (d, 2H, J=8.2 Hz), 7.40 (d, 2H, J=8.2 Hz), 7.10(s, 1H), 4.53 (s, 2H), 3.84 (d, 1H, J=11.3 Hz), 3.73-3.67 (m, 1H),3.60-3.55 (m, 1H), 3.43 (s, 3H), 3.30-3.27 (m, 1H), 3.20 (dd, 1H,J=13.6, 6.9 Hz), 2.93 (dd, 1H, J=12.5, 2.3 Hz), 2.77 (dd, 2H, J=8.3, 2.7Hz), 2.58 (dd, 1H, J=12.5, 10.4 Hz). LCMS (4) Rt=1.32 min; m/z (ESI⁺)432 (MH⁺).

Synthesis 194(S)-5-(5-(4-(2-Methoxyethoxy)phenyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-149)

Prepared using methods analogous to those in Synthesis 191, steps 191-F,191-G and 191-H.

¹H NMR (MeOD-d₄, 500 MHz) δ 8.87 (s, 1H), 8.58 (d, 1H, J=1.1 Hz), 7.74(s, 1H), 7.32 (d, 2H, J=8.7 Hz), 7.11 (s, 1H), 7.08 (d, 2H, J=8.7 Hz),4.19-4.17 (m, 2H), 3.94 (dd, 1H, J=12.1, 2.5 Hz), 3.80-3.78 (m, 3H),3.69-3.63 (m, 1H), 3.46 (s, 3H), 3.36-3.33 (m, 1H), 3.26 (dd, 1H,J=13.9, 6.7 Hz), 3.09 (d, 1H, J=11.2 Hz), 2.97-2.88 (m, 2H), 2.73 (dd,1H, J=12.5, 10.8 Hz). LCMS (4) Rt=1.47 min; m/z (ESI⁺) 462 (MH⁺).

Synthesis 195(S)-5-(5-(3-fluorophenyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-150)

Prepared using methods analogous to those in Synthesis 191, steps 191-F,191-G and 191-H.

¹H NMR (CDCl₃, 500 MHz) δ 8.65 (s, 1H), 8.40 (s, 1H), 7.77 (s, 1H), 7.38(dd, 1H, J=14.0, 8.0 Hz), 7.12-7.09 (m, 2H), 7.05-7.01 (m, 2H), 4.93 (t,1H, J=5.0 Hz), 3.78 (dt, 1H, J=11.0, 2.0 Hz), 3.67-3.62 (m, 1H), 3.52(dt, 1H, J=11.0, 7.0 Hz), 3.22 (ddd, 1 H, J=13.0, 6.0, 4.0 Hz), 3.12(ddd, 1H, J=13.0, 7.5, 5.0 Hz), 2.89 (dd, 1H, J=12.0, 2.0 Hz), 2.77 (dd,2H, J=7.5, 2.5 Hz), 2.60 (dd, 1H, J=12.0, 10.0 Hz). LCMS (4) Rt=1.36min; m/z (ESI⁺) 406 (MH⁺).

Synthesis 196(S)-5-(5-(4-Fluorophenyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-151)

Prepared using methods analogous to those in Synthesis 191, steps 191-F,191-G and 191-H.

¹H NMR (CDCl₃, 500 MHz) δ 8.72 (s, 1H), 8.39 (s, 1H), 7.73 (s, 1H),7.31-7.27 (m, 2H), 7.13-7.09 (m, 2H), 6.98 (s, 1H), 4.81 (t, 1H, J=5.3),3.77 (dt, 1H, J=11.5, 2.5, Hz), 3.65-3.61 (m, 1H), 3.52 (ddd, 1H, J,14.0, 6.5, 5.0 Hz), 3.20 (ddd, 1H, J=13.0, 6.0, 4.0 Hz), 3.10 (ddd, 1H,J=13.0, 7.5, 5.0 Hz), 2.89 (dd, 1H, J=12.0, 2.5 Hz), 2.78-2.76 (m, 2H),2.59 (dd, 1H, J=12.0, 10.0 Hz). LCMS (4) Rt=1.25 min; m/z (ESI⁺) 406(MH⁺).

Synthesis 197(S)-5-(5-(1-Methyl-1H-pyrazol-4-yl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-152)

Prepared using methods analogous to those in Synthesis 191, steps 191-F,191-G and 191-H.

¹H NMR (CDCl₃, 500 MHz) δ 8.81 (s, 1H), 8.38 (s, 1H), 7.76 (s, 1H), 7.54(s, 1H), 7.41 (s, 1H), 6.80 (s, 1H), 5.00 (t, 1H, J=5.0 Hz), 3.92 (s,3H), 3.81 (dt, 1H, J=11.5, 2.5 Hz), 3.67-3.62 (m, 1H), 3.54 (ddd, 1H,J=11.5, 10.0, 4.0 Hz), 3.20 (ddd, 1H, J=13.0, 6.5, 4.0 Hz), 3.11 (ddd,1H, J=13.0, 7.5, 4.5 Hz), 2.89 (dd, 1H, J=12.0, 2.5 Hz), 2.82-2.77 (m,1H), 2.62 (dd, 1H, J=12.0, 10.0 Hz). LCMS (4) Rt=1.31 min; m/z (ESI⁺)392 (MH⁺).

Synthesis 198(S)-5-(5-(3-Hydroxy-3-methylbut-1-ynyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-153)

Prepared using methods analogous to those in Synthesis 190, step 190-E,and Synthesis 189, steps 189-A and 189-B.

¹H NMR (MeOD-d₄, 500 MHz) δ 8.92 (d, 1H, J=1.3 Hz), 8.58 (d, 1H, J=1.4Hz), 7.96 (s, 1H), 7.06 (s, 1H), 3.92 (d, 1H, J=11 Hz), 3.78-3.73 (m,1H), 3.68-3.61 (m, 1H), 3.37 (dd, 1H, J=13.5, 4.4 Hz), 3.26 (dd, 1H,J=13.5, 7 Hz), 2.97 (dd, 1H, J=12.4, 2.1 Hz), 2.88-2.81 (m, 2H), 2.66(d, 1H, J=12.5, 10.5 Hz), 1.61 (s, 6H). LCMS (4) Rt=1.38 min; m/z (ESI⁺)394 (MH⁺).

Synthesis 199(S)-5-(5-(3-Methoxyprop-1-ynyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-154)

Prepared using methods analogous to those in Synthesis 190, steps 190-F,190-G and 190-H and Synthesis 188, steps 188-A and 188-B.

¹H NMR (MeOD-d₄, 500 MHz) δ 8.93 (s, 1H), 8.58 (s, 1H), 8.02 (s, 1H),7.10 (s, 1H), 4.41 (s, 2H), 3.93 (d, 1H, J=9.4 Hz), 3.79-3.75 (m, 1H),3.68-3.64 (m, 1H), 3.46 (s, 3H), 3.38 (dd, 1H, J=13.8, 4.6 Hz), 3.30(dd, 1H, J=13.8, 6.7 Hz), 3.00 (dd, 1H, J=12.6, 2.0 Hz), 2.87-2.85 (m,2H), 2.68 (dd, 1H, J=12.4, 10.8 Hz). LCMS (4) Rt=1.37 min; m/z (ESI⁺)380 (MH⁺).

Synthesis 200(S)-5-(5-(3-Methoxy-3-methylbut-1-ynyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-155)

Prepared from (R)-tert-butyl2-((2-chloro-5-iodopyridin-4-ylamino)methyl)morpholine-4-carboxylate(Synthesis 191-E) using methods analogous to those described inSynthesis 189, steps 189-A and 189-B.

¹H NMR (CDCl₃, 500 MHz) δ 8.75 (s, 1H), 8.41 (s, 1H), 7.99 (s, 1H), 6.85(s, 1H), 5.46 (t, 1H, J=5.0 Hz), 3.87-3.85 (m, 1H,), 3.73-3.68 (m, 1H),3.60 (td, 1H, J=11.0, 3.5 Hz), 3.37 (s, 3H), 3.26 (ddd, 1H, J=12.5, 6.0,4.0 Hz), 3.14 (ddd, 1H, J=12.5, 7.5, 4.0 Hz), 2.93-2.90 (m, 1H),2.87-2.76 (m, 2H), 2.69 (dd, 1H, J=12.0, 10.5 Hz), 1.52 (s, 6H). LCMS(4) Rt=1.55 min; m/z (ESI⁺) 408 (MH⁺).

Synthesis 201(R)-5-(5-(4-(Methoxymethyl)phenyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-156)

Prepared using methods analogous to those in Synthesis 192, steps 192-F,192-G and 192-H.

¹H NMR (MeOD-d₄, 500 MHz) δ 8.92 (s, 1H), 8.57 (s, 1H), 7.77 (s, 1H),7.48 (d, 2H, J=8.2 Hz), 7.40 (d, 2H, J=8.2 Hz), 1.86 (s, 2H), 3.85-3.82(m, 1H), 3.72-3.67 (m, 1H), 3.60-3.55 (m, 1H), 2.82 (s, 3H), 3.22-3.18(m, 1H), 2.93 (dd, 1H, J=2.3, 12.5 Hz), 2.78-2.76 (m, 2H), 2.58 (dd, 1H,J=10.4, 12.5 Hz). LCMS (4) Rt=1.36 min; m/z (ESI⁺) 432 [MH⁺].

Synthesis 202(R)-5-(5-(4-(2-Methoxyethoxy)phenyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-157)

Prepared using methods analogous to those in Synthesis 192, steps 192-F,192-G and 192-H.

LCMS (4) Rt=1.39 min; m/z (ESI⁺) 462 [MH⁺].

Synthesis 203(R)-5-(5-(3-hydroxy-3-methylbut-1-ynyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-158)

Prepared from (S)-tert-butyl2-((2-chloro-5-iodopyridin-4-ylamino)methyl)morpholine-4-carboxylate(Synthesis 192-E) using methods analogous to those described inSynthesis 189, steps 189-A and 189-B.

¹H NMR (MeOD-d₄, 500 MHz) δ 8.92 (s, 1H), 8.60 (s, 1H), 8.00 (s, 1H),7.16 (s, 1H), 4.14-4.12 (m, 1H), 4.03-3.92 (m, 1H), 3.83 (td, 1H, J=2.6,12.4 Hz), 3.56-3.38 (m, 2H), 3.36-3.33 (m, 2H), 3.27-3.08 (m, 2H), 2.98(t, 1H, J=11.8 Hz), 1.62 (s, 6H). LCMS Rt=1.25 min; m/z (ESI⁺) 394[MH⁺].

Synthesis 204(R)-5-(5-(3-Methoxypropyl)-4-(morpholin-2-ylmethylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile(Y-159)

Prepared using methods analogous to those in Synthesis 198 and Synthesis185.

¹H NMR (MeOD-d₄, 500 MHz) δ 8.78 (s, 1H), 8.55 (s, 1H), 7.72 (s, 1H),6.96 (s, 1H), 3.93 (dd, 1H, J=11.3, 1.7 Hz), 3.84-3.74 (m, 1H),3.70-3.61 (m, 1H), 3.45 (t, 2H, J=6.1 Hz), 3.39 (s, 3H), 3.37-3.28 (m,2H), 3.01 (d, 1H, J=12.4 Hz), 2.91-2.90 (m, 2H), 2.67-2.56 (m, 3H),1.86-1.81 (m, 2H). LCMS (4) Rt=1.72 min; m/z (ESI⁺) 384 [MH⁺].

Synthesis 205-A 5-Amino-3-methoxypyrazine-2-carbonitrile

5-Amino-3-chloropyrazine-2-carbonitrile (52 mg, 0.34 mmol) was suspendedin NaOMe/MeOH (2M, 2 mL). The reaction mixture was heated at 80° C. for30 min using microwave irradiation. After cooling, the mixture wasdiluted with MeOH (3 mL) and water (2 mL). The solvents wereconcentrated and the resulting precipitate was filtered off, washed withwater (3 mL) and dried in vacuo to give the title compound as a yellowsolid (33 mg, 58%).

¹H NMR (500 MHz, d₆-DMSO) δ 7.65 (2H, s, broad), 7.52 (1H, s) and 3.90(3H, s). LCMS (3B) Rt=2.60 min; m/z (ESI⁺) 151 [MH⁺].

Synthesis 205-B5-(6-Chloropyrimidin-4-ylamino)-3-methoxypyrazine-2-carbonitrile

5-Amino-3-methoxypyrazine-2-carbonitrile (9.2 mg, 0.061 mmol),4,6-dichioropyrimidine (10 mg, 0.067 mmol), lithiumbis(trimethylsilyl)amide (1M, 75 uL, 0.075 mmol), Pd₂(dba)₃ (3.5 mg,5.5% mol) and 2-(di-tert-butyl-phosphino)biphenyl (2 mg, 0.0067 mmol)were mixed in THF (0.5 mL). The reaction mixture was heated at 135° C.for 60 minutes using microwave irradiation. The crude product waspurified by preparative thin layer chromatography, eluting withEtOAc/n-hexane (1/2), to give the title compound as an oil (4.5 mg,28%).

¹H NMR (500 MHz, d₄-MeOD) δ 8.68 (1H, s), 8.61 (1H, s), 7.95 (1H, s),4.16 (3H, s). LCMS (3B) Rt=4.32 min; m/z (ESI⁺) 263 [MH⁺].

Synthesis 205-C tert-Butyl4-((6-(5-cyano-6-methoxypyrazin-2-ylamino)pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate

A solution of5-(6-chloropyrimidin-4-ylamino)-3-methoxypyrazine-2-carbonitrile (4.5mg, 0.017 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (4mg, 0.034 mmol) and triethylamine (12 uL, 0.085 mmol) in acetonitrile(1.5 mL) was heated at 145° C. for 90 min using microwave irradiation.The solvent was removed in vacuo and the crude mixture was purified bypreparative thin layer chromatography, eluting with dichloromethane/MeOH(10/1), to give the title compound as a yellow oil (3 mg, 40%).

¹H NMR (500 MHz, CDCl₃) δ 8.38 (1H, s), 8.30 (1H, s), 7.05 (1H, s),5.24-5.58 (1H+1H, m, NH), 4.15-4.26 (2H, m), 4.13 (3H, s), 3.18-3.32(2H, m), 2.64-2.84 (3H, m), 1.79-1.85 (2H, m), 1.46 (9H, s), 1.14-1.26(2H, m). LCMS (3B) Rt=4.87 min; m/z (ESI⁺) 441 [MH⁺].

Synthesis 205-D3-Methoxy-5-(6-(piperidin-4-ylmethylamino)pyrimidin-4-ylamino)-pyrazine-2-carbonitrile(Z-046)

TFA (0.1 mL) was added to a solution of tert-butyl4-((6-(5-cyano-6-methoxypyrazin-2-ylamino)-pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate(3 mg, 0.0068 mmol) in dichloromethane (3 mL) at room temperature. After2 hr, the solution was evaporated to dryness and purified by ionexchange on SCX-II acidic resin (500 mg), eluting with methanol then 2Mammonia-methanol. The basic fractions were combined and the solvent wasremoved in vacuo to give the title compound as yellow oil (1.5 mg, 65%).

¹H NMR (500 MHz, d₄-MeOD) δ 8.38 (1H, s), 8.22 (1H, s), 7.02 (1H, s),4.16 (3H, s), 3.20-3.30 (2H, m), 3.10-3.20 (4H, m), 2.62-2.76 (2H, m),1.78-1.88 (3H, m). LCMS (3B) Rt=2.02 min; m/z (ESI⁺) 341.2 [MH⁺].

Biological Methods

Measurement of Inhibition of CHK1 Kinase Function

CHK1 kinase function was measured in a DELFIA® assay in order to monitorphosphorylation of a CDC25C peptide using a specific phospho antibody.

The enzyme reaction was carried out in polypropylene plates (Greiner)using a reaction mix (25 μL) containing enzyme and peptide mix (CHK1, 1nM; Biotin-KKKVSRSGLYRSPSMPENLNRPR, 1 μM or 15 μL), ATP (30 μM or 5 μL)and either DMSO (2.5%) or test compound (5 μL) diluted to a give a rangeof concentrations (from 0 to 100 μM in 2.5% DMSO, final concentrations)in assay buffer (40 mM Tris, 40 mM NaCl, 2 mM MgCl₂, 1 mM DTT and 0.1%Tween 20). The reaction mixture was incubated for 30 minutes at roomtemperature and then stopped by the addition of buffer (125 μL)containing 40 mM EDTA, 0.05% Tween 20, 0.1% BSA in TBS (10× concentrate,Sigma). An aliquot (100 μL) of the stopped reaction mixture wastransferred to a black neutravidin-coated plate (Perbio) and incubatedfor 1 hour on a shaker (Titertek, Flow Laboratories) at roomtemperature. The plates were washed four times with wash buffer (25 mMTris (pH 8), 150 mM NaCl, and 0.1% Tween 20) (WellWash4, Thermo LifeSciences) and incubated for 1 hour as before with an antibody mixture(100 μL) consisting of anti-phospho CDC25C (1.25 nM, #9528, CellSignalling Technology) and europium-labelled anti-rabbit IgG (0.3 μg/mL,AD0105, PerkinElmer Life Sciences) diluted in DELFIA assay buffer(PerkinElmer Life Sciences). The plates were washed a further four timeswith wash buffer before the addition of enhancement solution (100μL/well, PerkinElmer Life Sciences). The plate was read on a Victor²1420 multilabel counter (Perkin Elmer Life Sciences) using atime-resolved measurement mode reading fluorescence at 615 nm.

Measurement of Cytotoxicity

HT29 colon carcinoma cells were obtained from ATCC (Rockville, Md.,USA). Cells were grown in DMEM supplemented with 10% foetal calf serumand containing L-glutamine 5 mM, glucose, penicillin, and streptomycin.Cells were grown at 37° C. in a dry 5% CO₂ atmosphere. Cytotoxicityassays were carried out in 96-well plates using quadruplicate wells foreach dose. Cells were seeded at 1.6×10³ per well in 160 μL medium andwere allowed to attach for 36 hours prior to treatment. Test compoundswere dissolved in DMSO at 10 mM and serially diluted in culture mediumto 5× final concentration prior to addition in a volume of 40 μl perwell. Cells were left for 4 doublings (96 hours) in the presence of thetest compounds and then fixed in 10% TCA for 30 minutes, washed inwater, and dried. The fixed cells were stained with Sulfurhodamine B(SRB, 0.4% in 1% acetic acid, Sigma, Dorset, UK) for 30 minutes, washedin 1% acetic acid, and dried. SRB was resolubilised in 10 mM Tris baseand the OD was measured at 490 nm. Results were expressed relative tountreated controls and the concentration of compound required to inhibitgrowth by 50% (SRB IC₅₀) was calculated.

Mitosis Inhibition Assay (MIA)

Checkpoint abrogation by CHK1 kinase function inhibitors in combinationwith genotoxic agents was assessed using a europium based ELISA assaydesigned to quantify the number of cells trapped in mitosis aftertreatment with a genotoxic agent (to induce G2 arrest) followed by atest compound in combination with nocodazole to abrogate this arrest.

HT29 cells were seeded at 10⁴ cells per well into 96 well plates in avolume of 160 μL and left to attach for 36 hours. Etoposide (10 mM stockin DMSO) was diluted in medium to 250 μM and then 40 μL was added toappropriate wells to give a final concentration of 50 μM and incubatedfor 1 hour. This treatment had previously been optimised to induce a G2arrest in 80% of cells 16 hours following treatment. After genotoxicdrug exposure, the medium was removed and replaced with fresh medium(160 μL). Cells were either untreated (untreated control or etoposidepre-treatment alone), exposed to nocodazole following etoposidepre-treatment or nocodazole alone (100 ng/mL final concentration), orexposed to increasing concentrations of test compound (200 μM-0.01 nMfinal concentration) in combination with nocodazole (100 ng/mL finalconcentration). Test compounds were added in 40 μL using quadruplicatewells for each dose. After 21 hours exposure, the medium was removed andcells were fixed in 4% formaldehyde in phosphate buffered saline (PBS,pH 7.4, pre-cooled to 4° C.) for 30 minutes at 4° C., followed by 100%methanol (pre-cooled to −20° C.) for 10 minutes at ambient temperature.Wells were washed with PBS and blocked with 5% dried milk (Marvel) inTris-buffered saline (TBS, pH 7.4) at 37° C. for 30 minutes. Each wellwas washed three times with water containing 0.1% tween 20. Primaryantibody (MPM-2, Upstate cat #05-368, 1 μg/mL in 5% milk in TBS) wasadded to each well and incubated overnight with shaking at 4° C. Primaryantibody was removed and wells were washed with water containing 0.1%Tween 20. The secondary antibody (europium labelled anti-mouse,Perkin-Elmer cat #AD0124, 333 ng/mL in assay buffer Perkin-Elmer cat#1244-111) was added to each well and incubated at 37° C. for 1 hour.Each well was washed with water 0.1% containing tween 20 and treatedwith enhancement solution (Perkin-Elmer cat #1244-105). Europiumemissions were counted on a Wallac, Victor² counter (Perkin-Elmer, BucksUK). Appropriate controls were included and results were expressed asthe concentration of test compound required to allow 50% of cells toenter mitosis (MIA IC₅₀).

Biological Data

Biological data were obtained using the CHK1 kinase function inhibitionassay described above for the following compounds: Y-001 through Y-039and Z-001 through Z-045.

For the CHK1 kinase function inhibition assay, all of the compounds hadIC50 values of less than 100 μM.

For the CHK1 kinase function inhibition assay, the following compoundshad IC50 values of 1 μM or less: Y-001, Y-003, Y-005, Y-007, Y-008,Y-010, Y-016, Y-019, Y-020, Y-021, Y-022, Y-023, Y-024, Y-025, Y-026,Y-027, Y-028, Y-029, Y-031, Y-032, Y-033, Y-034, Y-036, Y-037, Z-007,Z-008, Z-010, Z-011, Z-012, Z-016, Z-021, Z-022, Z-025, Z-026, Z-027,Z-029, Z-039.

For the CHK1 kinase function inhibition assay, the following compoundshad IC50 values of more than 1 μM and less than 10 μM: Y-004, Y-006,Y-009, Y-011, Y-012, Y-013, Y-015, Y-030, Y-038, Y-039, Z-004, Z-005,Z-006, Z-009, Z-013, Z-014, Z-015, Z-018, Z-019, Z-020, Z-024, Z-028,Z-031, Z-032, Z-038, Z-040, Z-041.

One compound, compound Y-003, has an IC50 value of 0.66 μM.

One compound, compound Z-016, has an IC50 value of 0.60 μM.

Biological data were obtained using the CHK1 kinase function inhibitionassay described above for the following compounds: Y-001 through Y-159and Z-001 through Z-046.

For the CHK1 kinase function inhibition assay, all of the compounds hadIC50 values of less than 100 μM.

For the CHK1 kinase function inhibition assay, the following compoundshad IC50 values of 0.1 μM or less: Y-007, Y-019, Y-020, Y-021, Y-022,Y-023, Y-025, Y-026, Y-027, Y-029, Y-032, Y-033, Y-037, Y-040, Y-041,Y-042, Y-047, Y-048, Y-053, Y-056, Y-058, Y-059, Y-060, Y-061, Y-062,Y-063, Y-064, Y-067, Y-070, Y-072, Y-073, Y-075, Y-076, Y-077, Y-078,Y-079, Y-080, Y-081, Y-082, Y-083, Y-084, Y-085, Y-086, Y-087, Y-095,Y-096, Y-098, Y-099, Y-100, Y-102, Y-103, Y-105, Y-107, Y-108, Y-110,Y-111, Y-112, Y-114, Y-115, Y-116, Y-117, Y-118, Y-119, Y-120, Y-122,Y-123, Y-124, Y-125, Y-126, Y-127, Y-128, Y-129, Y-130, Y-131, Y-135,Y-136, Y-137, Y-138, Y-139, Y-140, Y-141, Y-144, Y-145, Y-146, Y-147,Y-148, Y-149, Y-150, Y-151, Y-152, Y-153, Y-154, Y-155, Y-156, Y-157,Y-158, Y-159, Z-027.

For the CHK1 kinase function inhibition assay, the following compoundshad IC50 values of more than 0.1 μM and less than or equal to 1 μM:Y-001, Y-003, Y-005, Y-008, Y-010, Y-016, Y-024, Y-028, Y-031, Y-034,Y-036, Y-043, Y-044, Y-055, Y-057, Y-065, Y-066, Y-071, Y-088, Y-091,Y-092, Y-093, Y-094, Y-097, Y-101, Y-106, Y-109, Y-113, Y-121, Y-132,Y-133, Y-134, Y-142, Y-143, Z-007, Z-008, Z-010, Z-011, Z-012, Z-016,Z-021, Z-022, Z-025, Z-026, Z-029, Z-039.

For the CHK1 kinase function inhibition assay, the following compoundshad IC50 values of more than 1 μM and less than 10 μM: Y-004, Y-006,Y-009, Y-011, Y-012, Y-013, Y-015, Y-030, Y-038, Y-039, Y-045, Y-046,Y-050, Y-051, Y-052, Y-054, Y-068, Y-069, Y-074, Y-089, Y-090, Y-104,Z-004, Z-005, Z-006, Z-009, Z-013, Z-014, Z-015, Z-018, Z-019, Z-020,Z-024, Z-028, Z-031, Z-032, Z-038, Z-040, Z-041, Z-046.

The foregoing has described the principles, preferred embodiments, andmodes of operation of the present invention. However, the inventionshould not be construed as limited to the particular embodimentsdiscussed. Instead, the above-described embodiments should be regardedas illustrative rather than restrictive, and it should be appreciatedthat variations may be made in those embodiments by workers skilled inthe art without departing from the scope of the present invention.

REFERENCES

A number of patents and publications are cited above in order to morefully describe and disclose the invention and the state of the art towhich the invention pertains. Full citations for these references areprovided below. Each of these references is incorporated herein byreference in its entirety into the present disclosure, to the sameextent as if each individual reference was specifically and individuallyindicated to be incorporated by reference.

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1. A compound selected from compounds of the following formula, andpharmaceutically acceptable salts, chemically protected forms, andprodrugs thereof:

wherein: —X═ is independently —CR^(A5)═ or —N═; —R^(A5) is independently—H or -Q^(A5); —R^(A3) is independently —H or -Q^(A3); —R^(A4) isindependently —NH₂, -Q^(A4N); —OH, —O-Q^(A4O), —SH, or —S-Q^(A4S);—R^(B3) is independently —H or -Q^(B3); —R^(B5) is independently —H or-Q^(B5); and —R^(B6) is independently —H or -Q^(B6); and wherein:-Q^(A4N) is independently -Q^(A4N1) or -Q^(A4N2); and wherein: -Q^(A4N1)independently —NHRQ^(QN1) or —NR^(QN1) ₂; -Q^(A4N2) independently—NR^(QN2)R^(QN3); and wherein: each —R^(QN1) is independently: —R^(I1),—R^(I2), —R^(I3), —R^(I4), —R^(I5), —R^(I6), —R^(I7), —R^(I8),-L^(I)-R^(I4), -L^(I)-R^(I5), -L^(I)-R^(I6), -L^(I)-R^(I7), or-L^(I)-R^(I8); wherein: each —R^(I1) is independently saturatedaliphatic C₁₋₆alkyl; each —R^(I2) is independently aliphaticC₂₋₆alkenyl; each —R^(I3) is independently aliphatic C₂₋₆alkynyl; each—R^(I4) is independently saturated C₃₋₆cycloalkyl; each —R^(I5) isindependently C₃₋₆cycloalkenyl; each —R^(I6) is independentlynon-aromatic C₃₋₈heterocyclyl; each —R^(I7) is independentlyC₆₋₁₀carboaryl; each —R^(I8) is independently C₅₋₁₀heteroaryl; each-L^(I)- is independently saturated aliphatic C₁₋₃alkylene; and wherein:each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkenyl, non-aromatic C₃₋₈heterocyclyl, C₆₋₁₀carboaryl,C₅₋₁₀heteroaryl, and C₁₋₃alkylene is optionally substituted, forexample, with one or more substituents —R^(I9), wherein each —R^(I9) isindependently: —F, —Cl, —Br, —I, —R^(L1), —CF₃, —OCF₃, —OH, -L^(L)-OH,—O-L^(L)-OH, —OR^(L1), -L^(L)-OR^(L1), —O-L^(L)-OR^(L1), —SH, —SR^(L1),—CN, —NO₂, —NH₂, —NHR^(L1), —NR^(L1) ₂, —NR^(L2)R^(L3), -L^(L)-NH₂,-L^(L)-NHR^(L1), -L^(L)-NR^(L1) ₂, -L^(L)-NR^(L2)R^(L3), —O-L^(L)-NH₂,—O-L^(L)-NHR^(L1), —O-L^(L)-NR^(L1) ₂, —O-L^(L)-NR^(L2)R^(L3), —C(═O)OH,—C(═O)OR^(L1), —C(═O)NH₂, —C(═O)NHR^(L1), —C(═O)NR^(L1) ₂,—C(═O)NR^(L2)R^(L3), —NHC(═O)R^(L1), —NR^(L1)C(═O)R^(L1),—NHC(═O)OR^(L1), —NR^(L1)C(═O)OR^(L1), —OC(═O)NH₂, —OC(═O)NHR^(L1),—OC(═O)NR^(L1) ₂, —OC(═O)NR^(L2)R^(L3), —C(═O)R^(L1), —NHC(═O)NH₂,—NHC(═O)NHR^(L1), —NHC(═O)NR^(L1) ₂, —NHC(═O)NR^(L2)R^(L3),—NR^(L1)C(═O)NH₂, —NR^(L1)C(═O)NHR^(L1), —NR^(L1)C(═O)NR^(L1) ₂,—NR^(L1)C(═O)NR^(L2)R^(L3), —NHS(═O)₂R^(L1), —NR^(L1)S(═O)₂R^(L1),—S(═O)₂NH₂, —S(═O)₂NHR^(L1), —S(═O)₂NR^(L1) ₂, —S(═O)₂NR^(L2)R^(L3),—S(═O)R^(L1), —S(═O)₂R^(L1), —OS(═O)₂R^(L1), or —S(═O)₂OR^(L1); wherein:each -L^(L)- is independently saturated aliphatic C₁₋₅alkylene; in eachgroup —NR^(L2)R^(L3), R^(L2) and R^(L3), taken together with thenitrogen atom to which they are attached, form a 4-, 5-, 6-, or7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N,and the other of said exactly 2 ring heteroatoms is independently N orO; each —R^(L1) is independently: —R^(Z1), —R^(Z4), —R^(Z6), —R^(Z7),—R^(Z8), -L^(Z)-R^(Z4), -L^(Z)-R^(Z6), -L^(Z)-R^(Z7), or -L^(Z)-R^(Z8);wherein: each —R^(Z1) is independently saturated aliphatic C₁₋₆alkyl;each —R^(Z4) is independently saturated C₃₋₆cycloalkyl; each —R^(Z6) isindependently non-aromatic C₃₋₈heterocyclyl; each —R^(Z7) isindependently C₆₋₁₀carboaryl; each —R^(Z8) is independentlyC₅₋₁₀heteroaryl; each -L^(Z)- is independently saturated aliphaticC₁₋₃alkylene; and wherein: each C₁₋₆alkyl, C₃₋₆cycloalkyl, non-aromaticC₃₋₈heterocyclyl, C₆₋₁₀carboaryl, C₅₋₁₀heteroaryl, and C₁₋₃alkylene isoptionally substituted, for example, with one or more substituents—R^(Z9), wherein each —R^(Z9) is independently: —F, —Cl, —Br, —I,—R^(ZZ1), CF₃, —OCF₃, —OH, -L^(ZZ)-OH, —OR^(ZZ1), -L^(ZZ)-OR^(ZZ1), —SH,—SR^(ZZ1), —CN, —NO₂, —NH₂, —NHR^(ZZ1), —NR^(ZZ1) ₂, —NR^(ZZ2)R^(ZZ3),-L^(ZZ)NH₂, -L^(ZZ)-NHR^(ZZ1), L^(ZZ)-NR^(ZZ1) ₂,-L^(ZZ)-NR^(ZZ2)R^(ZZ3), —C(═O)OH, —C(═O)OR^(ZZ1), —C(═O)NH₂,—C(═O)NHR^(ZZ1), —C(═O)NR^(ZZ1) ₂, or —C(═O)NR^(ZZ2)R^(ZZ3); wherein:each —R^(ZZ1) is independently saturated aliphatic C₁₋₄alkyl, phenyl, orbenzyl; each -L^(ZZ)- is independently saturated aliphatic C₁₋₅alkylene;and in each group —NR^(ZZ2)R^(ZZ3), R^(ZZ2) and R^(ZZ3), taken togetherwith the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N,and the other of said exactly 2 ring heteroatoms is independently N orO; and wherein: in the group —NR^(QN2)R^(QN3), R^(QN2) and R^(QN3),taken together with the nitrogen atom to which they are attached, form a4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ringheteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2ring heteroatoms is N, and the other of said exactly 2 ring heteroatomsis independently N or O; and wherein: -Q^(A4O) is independently —R^(C1),wherein —R^(C1) is independently: —R^(D1), —R^(D2), —R^(D3), —R^(D4),—R^(D5), —R^(D6), —R^(D7), —R^(D8), -L^(D)-R^(D4), -L^(D)-R^(D5),-L^(D)-R^(D6), -L^(D)-R^(D7), or -L^(D)-R^(D8); wherein: each —R^(D1) isindependently saturated aliphatic C₁₋₆alkyl; each —R^(D2) isindependently aliphatic C₂₋₆alkenyl; each —R^(D3) is independentlyaliphatic C₂₋₆alkynyl; each —R^(D4) is independently saturatedC₃₋₆cycloalkyl; each —R^(D5) is independently C₃₋₆cycloalkenyl; each—R^(D6) is independently non-aromatic C₃₋₈heterocyclyl; each —R^(D7) isindependently C₆₋₁₀carboaryl; each —R^(D8) is independentlyC₅₋₁₀heteroaryl; each -L^(D)- is independently saturated aliphaticC₁₋₃alkylene; and wherein: each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, non-aromatic C₃₋₈heterocyclyl,C₆₋₁₀carboaryl, C₅₋₁₀heteroaryl, and C₁₋₃alkylene is optionallysubstituted, for example, with one or more substituents —R^(D9), whereineach —R^(D9) is independently: —F, —Cl, —Br, —I, —R^(E1); —CF₃, —OCF₃,—OH, -L^(E)-OH, —O-L^(E)-OH, —OR^(E1), -L^(E)-OR^(E1), —O-L^(E)-OR^(E1),—SH, —SR^(E1), —CN, —NO₂, —NH₂, —NHR^(E1), —NR^(E1) ₂, —NR^(E2)R^(E3),-L^(E)-NH₂, -L^(E)-NHR^(E1), -L^(E)-NR^(E1) ₂, -L^(E)-NR^(E2)R^(E3),—O-L^(E)-NH₂, —O-L^(E)-NHR^(E1), —O-L^(E)-NR^(E1) ₂,—O-L^(E)-NR^(E2)R^(E3), —C(═O)OH, —C(═O)OR^(E1), —C(═O)NH₂,—C(═O)NHR^(E1), —C(═O)NR^(E1) ₂, or —C(═O)NR^(E2)R^(E3); wherein: each—R^(E1) is independently saturated aliphatic C₁₋₄alkyl, phenyl, orbenzyl; each -L^(E)- is independently saturated aliphatic C₁₋₅alkylene;and in each group —NR^(E2)R^(E3), R^(E2) and R^(E3), taken together withthe nitrogen atom to which they are attached, form a 4-, 5-, 6-, or7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N,and the other of said exactly 2 ring heteroatoms is independently N orO; and wherein: -Q^(A4S) is independently —R^(F1), wherein —R^(F1) isindependently: —R^(G1), —R^(G2), —R^(G3), —R^(G4), —R^(G5), —R^(G6),—R^(G7), —R^(G8), -L^(G)-R^(G4), -L^(G)-R^(G5), -L^(G)-R^(G6),-L^(G)-R^(G7), or -L^(G)-R^(G8); wherein: each —R^(G1) is independentlysaturated aliphatic C₁₋₆alkyl; each —R^(G2) is independently aliphaticC₂₋₆alkenyl; each —R^(G3) is independently aliphatic C₂₋₆alkynyl; each—R^(G4) is independently saturated C₃₋₆cycloalkyl; each —R^(G5) isindependently C₃₋₆cycloalkenyl; each —R^(G6) is independentlynon-aromatic C₃₋₈heterocyclyl; each —R^(G7) is independentlyC₆₋₁₀carboaryl; each —R^(G8) is independently C₅₋₁₀heteroaryl; each-L^(G)- is independently saturated aliphatic C₁₋₃alkylene; and wherein:each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkenyl, non-aromatic C₃₋₈heterocyclyl, C₆₋₁₀carboaryl,C₅₋₁₀heteroaryl, and C₁₋₃alkylene is optionally substituted, forexample, with one or more substituents —R^(G9), wherein each —R^(G9) isindependently: —F, —Cl, —Br, —I, —R^(H1), —CF₃, —OCF₃, —OH, -L^(H)-OH,—O-L^(H)-OH, —OR^(H1), -L^(H)-OH, —O-L^(H)-OH, —SH, —SR^(H1), —CN, —NO₂,—NH₂, —NHR^(H1), —NR^(H1) ₂, —NR^(H2)R^(H3), -L^(H)-NH₂,-L^(H)-NHR^(H1), -L^(H)-NR^(H1) ₂, -L^(H)-NR^(H2)R^(H3), —O-L^(H)-NH₂,—O-L^(H)-NHR^(H1), —O-L^(H)-NR^(H1) ₂, —O-L^(H)-NR^(H2)R^(H3), —C(═O)OH,—C(═O)OR^(H1), —C(═O)NH₂, —C(═O)NHR^(H1), —C(═O)NR^(H1) ₂, or—C(═O)NR^(H2)R^(H3); wherein: each —R^(H1) is independently saturatedaliphatic C₁₋₄alkyl, phenyl, or benzyl; each -L^(H)- is independentlysaturated aliphatic C₁₋₅alkylene; and in each group —NR^(H2)R^(H3),R^(H2) and R^(H3), taken together with the nitrogen atom to which theyare attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring havingexactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one ofsaid exactly 2 ring heteroatoms is N, and the other of said exactly 2ring heteroatoms is independently N or O; and wherein: -Q^(A3) isindependently: —F, —Cl, —Br, —I, —R^(N1), —CF₃, —OCF₃, —OH, —OR^(N1),—SH, —SR^(N1), —NH₂, —NHR^(N1), —NR^(N1) ₂, or —NR^(N2)R^(N3); wherein:each —R^(N1) is independently saturated aliphatic C₁₋₆alkyl; and in eachgroup —NR^(N2)R^(N3), R^(N2) and R^(N3), taken together with thenitrogen atom to which they are attached, form a 4-, 5-, 6-, or7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N,and the other of said exactly 2 ring heteroatoms is independently N orO; wherein: -Q^(A5) is independently: —F, —Cl, —Br, —I, —R^(J1), —CF₃,—OCF₃, —OH, -L^(J)-OH, —O-L^(J)-OH, —OR^(J1), -L^(J)-OR^(J1),—O-L^(J)-OR^(J1), —SH, —SR^(J1), —CN, —NO₂, —NH₂, —NHR^(J1), —NR^(J1) ₂,—NR^(J2)R^(J3), -L^(J)-NH₂, -L^(J)-NHR^(J1), -L^(J)-NR^(J1) ₂,-L^(J)-NR^(J2)R^(J3), —O-L^(J)-NH₂, —O-L^(J)-NHR^(J1), —O-L^(J)-NR^(J1)₂, —O-L^(J)-NR^(J2)R^(L3), —C(═O)OH, —C(═O)OR^(J1), —C(═O)NH₂,—C(═O)NHR^(J1), —C(═O)NR^(J1) ₂, —C(═O)NR^(J2)R^(J3), —NHC(═O)R^(J1),—NR^(J1)C(═O)R^(J1), —NHC(═O)OR^(J1), —NR^(J1)C(═O)OR^(J1), —OC(═O)NH₂,—OC(═O)NHR^(J1), —OC(═O)NR^(J1) ₂, —OC(═O)NR^(J2)R^(J3), —C(═O)R^(J1),—NHC(═O)NH₂, —NHC(═O)NHR^(J1), —NHC(═O)NR^(J1) ₂, —NHC(═O)NR^(J2)R^(J3),—NR^(J1)C(═O)NH₂, —NR^(J1)C(═O)NHR^(J1), —NR^(J1)C(═O)NR^(J1) ₂,—NR^(J1)C(═O)NR^(J2)R^(J3), —NHS(═O)₂R^(J1), —NR^(J1)S(═O)₂R^(J1),—S(═O)₂NH₂, —S(═O)₂NHR^(J1), —S(═O)₂NR^(J1) ₂, —S(═O)₂NR^(J2)R^(J3),—S(═O)R^(J1), —S(═O)₂R^(J1), —OS(═O)₂R^(J1), or —S(═O)₂OR^(J1); wherein:each -L^(J)- is independently saturated aliphatic C₁₋₅alkylene; in eachgroup —NR^(J2)R^(J3), R^(J2) and R^(J3), taken together with thenitrogen atom to which they are attached, form a 4-, 5-, 6-, or7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N,and the other of said exactly 2 ring heteroatoms is independently N orO; each —R^(J1) is independently: —R^(K1), —R^(K2), —R^(K3), —R^(K4),—R^(K5), —R^(K6), —R^(K7), —R^(K8), —L^(K)-R^(K4), -L^(K)-R^(K5),-L^(K)-R^(K6), -L^(K)-R^(K7), or -L^(K)-R^(K8); wherein: each —R^(K1) isindependently saturated aliphatic C₁₋₆alkyl; each —R^(K2) isindependently aliphatic C₂₋₆alkenyl; each —R^(K3) is independentlyaliphatic C₂₋₆alkynyl; each —R^(K4) is independently saturatedC₃₋₆cycloalkyl; each —R^(K5) is independently C₃₋₆cycloalkenyl; each—R^(K6) is independently non-aromatic C₃₋₈heterocyclyl; each —R^(K7) isindependently C₆₋₁₀carboaryl; each —R^(K8) is independentlyC₅₋₁₀heteroaryl; each -L^(K)- is independently saturated aliphaticC₁₋₃alkylene; and wherein: each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, non-aromatic C₃₋₈heterocyclyl,C₆₋₁₀carboaryl, C₅₋₁₀heteroaryl, and C₁₋₃alkylene is optionallysubstituted, for example, with one or more substituents —R^(K9), whereineach —R^(K9) is independently: —F, —Cl, —Br, —I, —R^(M1), —CF₃, —OCF₃,—OH, -L^(M)-OH, —O-L^(M)-OH, —OR^(M1), -L^(M)-OR^(M1), —O-L^(M)-OR^(M1),—SH, —SR^(M1), —CN, —NO₂, —NH₂, —NHR^(M1), —NR^(M1) ₂, —NR^(M2)R^(M3),-L^(M)-NH₂, -L^(M)-NHR^(M1), -L^(M)-NR^(M1) ₂, -L^(M)-NR^(M2)R^(M3),—C(═O)OH, —C(═O)OR^(M1), —C(═O)NH₂, —C(═O)NHR^(M1), —C(═O)NR^(M1) ₂, or—C(═O)NR^(M2)R^(M3); wherein: each —R^(M1) is independently saturatedaliphatic C₁₋₄alkyl, phenyl, or benzyl; each -L^(M)- is independentlysaturated aliphatic C₁₋₅alkylene; and in each group —NR^(M2)R^(M3),R^(M2) and R^(M3), taken together with the nitrogen atom to which theyare attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring havingexactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one ofsaid exactly 2 ring heteroatoms is N, and the other of said exactly 2ring heteroatoms is independently N or O; and wherein: -Q^(B3) isindependently: —F, —Cl, —Br, —I, —R^(Q1), —CF₃, —OCF₃, —OH, —OR^(Q1),—SH, —SR^(Q1), —NH₂, —NHR^(Q1), —NR^(Q1) ₂, or —NR^(Q2)R^(Q3); wherein:each —R^(Q1) is independently saturated aliphatic C₁₋₆alkyl; and in eachgroup —NR^(Q2)R^(Q3), R^(Q2) and R^(Q3), taken together with thenitrogen atom to which they are attached, form a 4-, 5-, 6-, or7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N,and the other of said exactly 2 ring heteroatoms is independently N orO; and wherein: -Q^(B5) is independently: —F, —Cl, —Br, —I, —R^(T1),—CF₃, —OCF₃, —OH, -L^(T)-OH, —O-L^(T)-OH, —OR^(T1), -L^(T)-OR^(T1),—O-L^(T)-OR^(T1), —SH, —SR^(T1), —CN, —NO₂, —NH₂, —NHR^(T1), —NR^(T1) ₂,—NR^(T2)R^(T3), -L^(T)-NH₂, -L^(T)-NHR^(T1), -L^(T)-NR^(T1) ₂,-L^(T)-NR^(T2)R^(T3), —O-L^(T)-NH₂, —O-L^(T)-NHR^(T1), —O-L^(T)-NR^(T1)₂, —O-L^(T)-NR^(T2)R^(T3), —C(═O)OH, —C(═O)OR^(T1), —C(═O)NH₂,—C(═O)NHR^(T1), —C(═O)NR^(T1) ₂, —C(═O)NR^(T2)R^(T3), —NHC(═O)R^(T1),—NR^(T1)C(═O)R^(T1), —NHC(═O)OR^(T1), —NR^(T1)C(═O)OR^(T1), —OC(═O)NH₂,—OC(═O)NHR^(T1), —OC(═O)NR^(T1) ₂, —OC(═O)NR^(T2)R^(T3), —C(═O)R^(T1),—NHC(═O)NH₂, —NHC(═O)NHR^(T1), —NHC(═O)NR^(T1) ₂, —NHC(═O)NR^(T2)R^(T3),—NR^(T1)C(═O)NH₂, —NR^(T1)C(═O)NHR^(T1), —NR^(T1)C(═O)NR^(T1) ₂,—NR^(T1)C(═O)NR^(T2)R^(T3), —NHS(═O)₂R^(T1), —NR^(T1)S(═O)₂R^(T1),—S(═O)₂NH₂, —S(═O)₂NHR^(T1), —S(═O)₂NR^(T1) ₂, —S(═O)₂NR^(T2)R^(T3),—S(═O)R^(T1), —S(═O)₂R^(T1), —OS(═O)₂R^(T1), or —S(═O)₂OR^(T1); wherein:each -L^(T)- is independently saturated aliphatic C₁₋₅alkylene; in eachgroup —NR^(T2)R^(T3), R^(T2) and R^(T3), taken together with thenitrogen atom to which they are attached, form a 4-, 5-, 6-, or7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N,and the other of said exactly 2 ring heteroatoms is independently N orO; each —R^(T1) is independently: —R^(U1), —R^(U2), —R^(U3), —R^(U4),—R^(U5), —R^(U6), —R^(U7), —R^(U8), -L^(U)-R^(U4), -L^(U)-R^(U5),-L^(U)-R^(U6), -L^(U)R^(U7), or -L^(U)-R^(U8); wherein: each —R^(U1) isindependently saturated aliphatic C₁₋₆alkyl; each —R^(U2) isindependently aliphatic C₂₋₆alkenyl; each —R^(U3) is independentlyaliphatic C₂₋₆alkynyl; each —R^(U4) is independently saturatedC₃₋₆cycloalkyl; each —R^(U5) is independently C₃₋₆cycloalkenyl; each—R^(U6) is independently non-aromatic C₃₋₈heterocyclyl; each —R^(U7) isindependently C₆₋₁₀carboaryl; each —R^(U8) is independentlyC₅₋₁₀heteroaryl; each -L^(U)- is independently saturated aliphaticC₁₋₃alkylene; and wherein: each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, non-aromatic C₃₋₈heterocyclyl,C₆₋₁₀carboaryl, C₅₋₁₀heteroaryl, and C₁₋₃alkylene is optionallysubstituted, for example, with one or more substituents —R^(U9), whereineach —R^(U9) is independently: —F, —Cl, —Br, —I, —R^(V1), —CF₃, —OCF₃,—OH, -L^(V)-OH, —OR^(V1), -L^(V)-OR^(V1), —SH, —SR^(V1), —CN, —NO₂,—NH₂, —NHR^(V1), —NR^(V1) ₂, —NR^(V2)R^(V3), -L^(V)-NH₂,-L^(V)-NHR^(V1), -L^(V)-NR^(V1) ₂, -L^(V)-NR^(V2)R^(V3), —C(═O)OH,—C(═O)OR^(V1), —C(═O)NH₂, —C(═O)NHR^(V1), —C(═O)NR^(V1) ₂, or—C(═O)NR^(V2)R^(V3); wherein: each —R^(V1) is independently saturatedaliphatic C₁₋₄alkyl, phenyl, or benzyl; each -L^(V)- is independentlysaturated aliphatic C₁₋₅alkylene; and in each group —NR^(V2)R^(V3),R^(V2) and R^(V3), taken together with the nitrogen atom to which theyare attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring havingexactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one ofsaid exactly 2 ring heteroatoms is N, and the other of said exactly 2ring heteroatoms is independently N or O; and wherein: -Q^(B6) isindependently: —R^(W1), —CF₃, —OCF₃, —OH, -L^(W)-OH, —O-L^(W)-OH,—OR^(W1), -L^(W)-OR^(W1), —O-L^(W)-OR^(W1), —SH, —SR^(W1), —CN, —NO₂,—NH₂, —NHR^(W1), —NR^(W1) ₂, —NR^(W2)R^(W3), -L^(W)-NH₂,-L^(W)-NHR^(W1), -L^(W)-NR^(W1) ₂, -L^(W)-NR^(W2)R^(W3), —O-L^(W)-NH₂,—O-L^(W)-NHR^(W1), —O-L^(W)-NR^(W1) ₂, —O-L^(W)-NR^(W2)R^(W3), —C(═O)OH,—C(═O)OR^(W1), —C(═O)NH₂, —C(═O)NHR^(W1), —C(═O)NR^(W1) ₂,—C(═O)NR^(W2)R^(W3), —NHC(═O)R^(W1), —NR^(W1)C(═O)R^(W1),—NHC(═O)OR^(W1), —NR^(W1)C(═O)OR^(W1), —OC(═O)NH₂, —OC(═O)NHR^(W1),—OC(═O)NR^(W1) ₂, —OC(═O)NR^(W2)R^(W3) —C(═O)R^(W1), —NHC(═O)NH₂,—NHC(═O)NHR^(W1), —NHC(═O)NR^(W1) ₂, —NHC(═O)NR^(W2)R^(W3),—NR^(W1)C(═O)NH₂, —NR^(W1)C(═O)NHR^(W1), —NR^(W1)C(═O)NR^(W1) ₂,—NR^(W1)C(═O)NR^(W2)R^(W3), —NHS(═O)₂R^(W1), —NR^(W1)S(═O)₂R^(W1),—S(═O)₂NH₂, —S(═O)₂NHR^(W1), —S(═O)₂NR^(W1) ₂, —S(═O)₂NR^(W2)R^(W3),—S(═O)R^(W1), —S(═O)₂R^(W1), —OS(═O)₂R^(W1), or —S(═O)₂OR^(W1); wherein:each -L^(W)-is independently saturated aliphatic C₁₋₅alkylene; in eachgroup —NR^(W2)R^(W3), R^(W2) and R^(W3), taken together with thenitrogen atom to which they are attached, form a 4-, 5-, 6-, or7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N,and the other of said exactly 2 ring heteroatoms is independently N orO; each —R^(W1) is independently: —R^(X1), —R^(X2), —R^(X3), —R^(X5),—R^(X6), —R^(X7), —R^(R8), -L^(X)-R^(X4), -L^(X)-R^(X5), -L^(X)-R^(X6),-L^(X)-R^(X7), or -L^(X)-R^(X8); wherein: each —R^(X1) is independentlysaturated aliphatic C₁₋₆alkyl; each —R^(X2) is independently aliphaticC₂₋₆alkenyl; each —R^(X3) is independently aliphatic C₂₋₆alkynyl; each—R^(X4) is independently saturated C₃₋₆cycloalkyl; each —R^(X5) isindependently C₃₋₆cycloalkenyl; each —R^(X6) is independentlynon-aromatic C₃₋₈heterocyclyl; each —R^(X7) is independentlyC₆₋₁₀carboaryl; each —R^(X8) is independently C₅₋₁₀heteroaryl; each-L^(X)- is independently saturated aliphatic C₁₋₃alkylene; and wherein:each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkenyl, non-aromatic C₃₋₈heterocyclyl, C₆₋₁₀carboaryl,C₅₋₁₀heteroaryl, and C₁₋₃alkylene is optionally substituted, forexample, with one or more substituents —R^(X9), wherein each —R^(X9) isindependently: —F, —Cl, —Br, —I, —R^(Y1), —CF₃, —OCF₃, —OH, -L^(Y)-OH,—OR^(Y1), -L^(Y)-OR^(Y1), —SH, —SR^(Y1), —CN, —NO₂, —NH₂, —NHR^(Y1),—NR^(Y1) ₂, —NR^(Y2)R^(Y3), -L^(Y)-NH₂, -L^(Y)-NHR^(Y1), -L^(Y)-NR^(Y1)₂,-L^(Y)-NR^(Y2)R^(Y3), —C(═O)OH, —C(═O)OR^(Y1), —C(═O)NH₂,—C(═O)NHR^(Y1), —C(═O)NR^(Y1) ₂, or —C(═O)NR^(Y2)R^(Y3); wherein: each—R^(Y1) is independently saturated aliphatic C₁₋₄alkyl, phenyl, orbenzyl; each -L^(Y)- is independently saturated aliphatic C₁₋₅alkylene;and in each group —NR^(Y2)R^(Y3), R^(Y2) and R^(Y3), taken together withthe nitrogen atom to which they are attached, form a 4-, 5-, 6-, or7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N,and the other of said exactly 2 ring heteroatoms is independently N orO.
 2. A compound according to claim 1, wherein —X═ is independently—CR^(A5)═.
 3. compound according to claim 1, wherein —X═ isindependently —N═. 4-296. (canceled)
 297. A compound according to claim1, selected from the following compounds, and pharmaceuticallyacceptable salts, chemically protected forms, and prodrugs thereof:Compound Nos. YY-001 through YY-159.
 298. A compound according to claim1, selected from the following compounds, and pharmaceuticallyacceptable salts, chemically protected forms, and prodrugs thereof:Compound Nos. ZZ-001 through ZZ-046.
 299. A pharmaceutical compositioncomprising a compound according to claim 1, and a pharmaceuticallyacceptable carrier or diluent.
 300. A method of preparing apharmaceutical composition comprising the step of admixing a compoundaccording to claim 1, and a pharmaceutically acceptable carrier ordiluent. 301-315. (canceled)
 316. A method of treatment of a disease orcondition that is mediated by CHK1 comprising administering to a subjectin need of treatment a therapeutically-effective amount of a compoundaccording to claim
 1. 317. A method of treatment of a disease orcondition that is ameliorated by the inhibition of CHK1 kinase functioncomprising administering to a subject in need of treatment atherapeutically-effective amount of a compound according to claim 1.318. A method of treatment of a proliferative condition comprisingadministering to a subject in need of treatment atherapeutically-effective amount of a compound according to claim 1.319. A method of treatment of cancer comprising administering to asubject in need of treatment a therapeutically-effective amount of acompound according to claim
 1. 320. A method of treatment of lungcancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, orglioma comprising administering to a subject in need of treatment atherapeutically-effective amount of a compound according to claim 1.321. A method according to claim 1, wherein the treatment furthercomprises administering to the subject one or more other agents selectedfrom: (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damagingagent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targetedagent; and (e) ionising radiation.
 322. A method of inhibiting CHK1kinase function, in vitro or in vivo, comprising contacting the cellwith an effective amount of a compound according to claim
 1. 323. Amethod of inhibiting CHK1 kinase function in a cell, in vitro or invivo, comprising contacting the cell with an effective amount of acompound according to claim
 1. 324. A method of inhibiting cellproliferation, inhibiting cell cycle progression, promoting apoptosis,or a combination of one or more these, in vitro or in vivo, comprisingcontacting the cell with an effective amount of a compound according toclaim 1.